Fused Imidazole Derivatives Useful as IDO Inhibitors

ABSTRACT

Presently provided are IDO inhibitors and pharmaceutical compositions thereof, useful for modulating an activity of indoleamine 2,3-dioxygenase; treating indoleanine 2,3-dioxygenase (IDO) mediated immunosuppression; treating a medical conditions that benefit from the inhibition of enzymatic activity of indoleamine-2,3-dioxygenase; enhancing the effectiveness of an anti-cancer treatment comprising administering an anti-cancer agent; treating tumor-specific immunosuppression associated with cancer; and treating immunosupression associated with an infectious disease.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of the filing date of U.S.Provisional Application Ser. No. 61/475,788, filed Apr. 15, 2011, whichis hereby incorporated by reference in its entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present disclosure relates to compounds and methods for inhibitionof indoleamine 2,3-dioxygenase; further the disclosure relates to methodof treatment of diseases and disorders mediated by indoleamine2,3-dioxygenase.

2. Summary of the Related Art

Tryptophan (Trp) is an essential amino acid required for thebiosynthesis of proteins, niacin and the neurotransmitter5-hydroxytryptamine (serotonin). The enzyme indoleamine 2,3-dioxygenase(also known as INDO or IDO) catalyzes the first and rate limiting stepin the degradation of L-tryptophan to N-formyl-kynurenine. In humancells, IFN-y stimulation induces activation of IDO, which leads to adepletion of Trp, thereby arresting the growth of Trp-dependentintracellular pathogens such as Toxoplasma gondii and Chlamydiatrachomatis. IDO activity also has an antiproliferative effect on manytumor cells, and IDO induction has been observed in vivo duringrejection of allogeneic tumors, indicating a possible role for thisenzyme in the tumor rejection process.

It has been observed that HeLa cells co-cultured with peripheral bloodlymphocytes (PBLs) acquire an immunoinhibitory phenotype throughup-regulation of IDO activity. A reduction in PBL proliferation upontreatment with interleukin-2 (IL-2) was believed to result from IDOreleased by the tumor cells in response to IFN-y secretion by the PBLs.This effect was reversed by treatment with 1-methyl-tryptophan (1MT), aspecific IDO inhibitor. It was proposed that IDO activity in tumor cellsmay serve to impair antitumor responses (Logan, et al., 2002,Immunology, 105: 478-87).

Several lines of evidence suggest that IDO is involved in induction ofimmune tolerance. Studies of mammalian pregnancy, tumor resistance,chronic infections and autoimmune diseases have shown that cellsexpressing IDO can suppress T-cell responses and promote tolerance.Accelerated Trp catabolism has been observed in diseases and disordersassociated with cellular immune activation, such as infection,malignancy, autoimmune diseases and AIDS, as well as during pregnancy.It was proposed that IDO is induced chronically by HIV infection, and isfurther increased by opportunistic infections, and that the chronic lossof Trp initiates mechanisms responsible for cachexia, dementia anddiarrhea and possibly immunosuppression of AIDS patients (Brown, et al.,1991, Adv. Exp. Med. Biol., 294: 425-35). To this end, it has recentlybeen shown that IDO inhibition can enhance the levels of virus-specificT cells and, concomitantly, reduce the number of virally infectedmacrophages in a mouse model of HIV (Portula et al., 2005, Blood,106:2382-90).

IDO is believed to play a role in the immunosuppressive processes thatprevent fetal rejection in utero. More than 40 years ago, it wasobserved that, during pregnancy, the genetically disparate mammalianconceptus survives in spite of what would be predicted by tissuetransplantation immunology (Medawar, 1953, Symp. Soc. Exp. Biol. 7:320-38). Anatomic separation of mother and fetus and antigenicimmaturity of the fetus cannot fully explain fetal allograft survival.Recent attention has focused on immunologic tolerance of the mother.Because IDO is expressed by human syncytiotrophoblast cells and systemictryptophan concentration falls during normal pregnancy, it washypothesized that IDO expression at the maternal-fetal interface isnecessary to prevent immunologic rejection of the fetal allografts. Totest this hypothesis, pregnant mice (carrying syngeneic or allogeneicfetuses) were exposed to 1MT, and a rapid, T cell-induced rejection ofall allogeneic concepti was observed. Thus, by catabolizing tryptophan,the mammalian conceptus appears to suppress T-cell activity and defendsitself against rejection, and blocking tryptophan catabolism duringmurine pregnancy allows maternal T cells to provoke fetal allograftrejection (Munn, et al., 1998, Science 281: 1191-3).

Further evidence for a tumoral immune resistance mechanism based ontryptophan degradation by IDO comes from the observation that most humantumors constitutively express IDO, and that expression of IDO byimmunogenic mouse tumor cells prevents their rejection by preimmunizedmice. This effect is accompanied by a lack of accumulation of specific Tcells at the tumor site and can be partly reverted by systemic treatmentof mice with an inhibitor of IDO, in the absence of noticeable toxicity.Thus, it was suggested that the efficacy of therapeutic vaccination ofcancer patients might be improved by concomitant administration of anIDO inhibitor (Uyttenhove et al., 2003, Nature Med., 9: 1269-74). It hasalso been shown that the IDO inhibitor, 1-MT, can synergize withchemotherapeutic agents to reduce tumor growth in mice, suggesting thatIDO inhibition may also enhance the anti-tumor activity of conventionalcytotoxic therapies (Muller et al., 2005, Nature Med., 11:312-9).

One mechanism contributing to immunologic unresponsiveness toward tumorsmay be presentation of tumor antigens by tolerogenic host APCs. A subsetof human IDO-expressing antigen-presenting cells (APCs) that coexpressedCD123 (IL3RA) and CCR6 and inhibited T-cell proliferation have also beendescribed. Both mature and immature CD123-positive dendritic cellssuppressed T-cell activity, and this IDO suppressive activity wasblocked by 1MT (Munn, et al., 2002, Science 297: 1867-70). It has alsobeen demonstrated that mouse tumor-draining lymph nodes (TDLNs) containa subset of plasmacytoid dendritic cells (pDCs) that constitutivelyexpress immunosuppressive levels of IDO. Despite comprising only 0.5% oflymph node cells, in vitro, these pDCs potently suppressed T cellresponses to antigens presented by the pDCs themselves and also, in adominant fashion, suppressed T cell responses to third-party antigenspresented by nonsuppressive APCs. Within the population of pDCs, themajority of the functional IDO-mediated suppressor activity segregatedwith a novel subset of pDCs coexpressing the B-lineage marker CD19.Thus, it was hypothesized that IDO-mediated suppression by pDCs in TDLNscreates a local microenvironment that is potently suppressive of hostantitumor T cell responses (Munn, et al., 2004, J. Clin. Invest.,114(2): 280-90).

IDO degrades the indole moiety of tryptophan, serotonin and melatonin,and initiates the production of neuroactive and immunoregulatorymetabolites, collectively known as kynurenines. By locally depletingtryptophan and increasing proapoptotic kynurenines, IDO expressed bydendritic cells (DCs) can greatly affect T-cell proliferation andsurvival. IDO induction in DCs could be a common mechanism of deletionaltolerance driven by regulatory T cells. Because such tolerogenicresponses can be expected to operate in a variety of physiopathologicalconditions, tryptophan metabolism and kynurenine production mightrepresent a crucial interface between the immune and nervous systems(Grohmann, et al., 2003, Trends Immunol., 24: 242-8).

Small molecule inhibitors of IDO are being developed to treat or preventIDO-related diseases such as those described above. For example, PCTPublication WO 99/29310 reports methods for altering T cell-mediatedimmunity comprising altering local extracellular concentrations oftryptophan and tryptophan metabolites, using an inhibitor of IDO such as1-methyl-DL-tryptophan, p-(3-benzofuranyl)-DL-alanine,p-[3-benzo[b]thienyl]-DL-alanine, and 6-nitro-L-tryptophan) (Munn,1999). Reported in WO 03/087347, also published as European Patent1501918, are methods of making antigen-presenting cells for enhancing orreducing T cell tolerance (Munn, 2003). Compounds havingindoleamine-2,3-dioxygenase (IDO) inhibitory activity are furtherreported in WO 2004/094409; and U.S. Patent Application Publication No.2004/0234623 is directed to methods of treating a subject with a canceror an infection by the administration of an inhibitor ofindoleamine-2,3-dioxygenase in combination with other therapeuticmodalities.

In light of the experimental data indicating a role for IDO inimmunosuppression, tumor resistance and/or rejection, chronicinfections, HIV-infection, AIDS (including its manifestations such ascachexia, dementia and diarrhea), autoimmune diseases or disorders (suchas rheumatoid arthritis), and immunologic tolerance and prevention offetal rejection in utero, therapeutic agents aimed at suppression oftryptophan degradation by inhibiting IDO activity are desirable.Inhibitors of IDO can be used to activate T cells and therefore enhanceT cell activation when the T cells are suppressed by pregnancy,malignancy or a virus such as HIV. Inhibition of IDO may also be animportant treatment strategy for patients with neurological orneuropsychiatric diseases or disorders such as depression. Thecompounds, compositions and methods herein help meet the current needfor IDO modulators.

SUMMARY OF THE INVENTION

In one aspect, the invention comprises compounds according to theformula (I),

wherein R¹, R², n and α are each defined herein.

In another aspect, the invention comprises compounds according to theformula (II),

wherein R¹, R³, R^(C), and n are each defined herein.

In another aspect pharmaceutical compositions are provided comprising apharmaceutically acceptable excipient, diluent, or carrier, and acompound according to formula (I) or (II).

In another aspect methods are provided for (a) modulating an activity ofindoleamine 2,3-dioxygenase comprising contacting an indoleamine2,3-dioxygenase with a modulation effective amount of a compoundaccording to formula (I) or (II), or a pharmaceutical compositioncomprising a compound according to formula (I) or (II); (b) treatingindoleamine 2,3-dioxygenase (IDO) mediated immunosuppression in asubject in need thereof, comprising administering an effectiveindoleamine 2,3-dioxygenase inhibiting amount of a compound according toformula (I) or (II), or a pharmaceutical composition comprising acompound according to formula (I) or (II); (c) treating a medicalcondition that benefits from the inhibition of enzymatic activity ofindoleamine-2,3-dioxygenase comprising administering an effectiveindoleamine 2,3-dioxygenase inhibiting amount of a compound according toformula (I) or (II), or a pharmaceutical composition comprising acompound according to formula (I) or (II); (d) enhancing theeffectiveness of an anti-cancer treatment comprising administering ananti-cancer agent and a compound according to formula (I) or (II), or apharmaceutical composition comprising a compound according to formula(I) or (II); (e) treating tumor-specific immunosuppression associatedwith cancer comprising administering an effective indoleamine2,3-dioxygenase inhibiting amount of a compound according to formula (I)or (II), or a pharmaceutical composition comprising a compound accordingto formula (I) or (II); and (f) treating immunosupression associatedwith an infectious disease, e.g., HIV-1 infection, comprisingadministering an effective indoleamine 2,3-dioxygenase inhibiting amountof a compound according to formula (I) or (II), or a pharmaceuticalcomposition comprising a compound according to formula (I) or (II).

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the absolute configuration of a diasteromer of the HBr saltof compound 1417 as confirmed by X-ray crystallography.

DETAILED DESCRIPTION OF THE INVENTION

In one aspect, the invention provides compounds of formula (I),

-   or a pharmaceutically acceptable salt thereof, wherein-   bond α is a single or double bond;-   n is 0, 1, 2, 3, or 4;-   each R¹ is independently halogen, cyano, nitro, C₁₋₆alkyl,    C₁₋₆haloalkyl, —OR, —N(R)₂, —SR, —C(O)OR, —C(O)N(R)₂, —C(O)R,    —S(O)R, —S(O)OR, —S(O)N(R)₂, —S(O)₂R, —S(O)₂OR, —S(O)₂N(R)₂,    —OC(O)R, —OC(O)OR, —OC(O)N(R)₂, —N(R)C(O)R, —N(R)C(O)OR, or    —N(R)C(O)N(R)₂;-   R² is —C₁₋₄alkyl-R^(A) or —C₂₋₄alkenyl-R³ when bond a is a single    bond; and-   R² is ═C(H)R^(A) when bond α is a double bond;-   wherein    -   R^(A) is —CN, —C(O)R³, —C(O)OR³, —C(O)N(R³)(R^(C)),        —C(OR^(B))(R³)(R^(C)), —C(NHR^(B))(R³)(R^(C)), or        —C(═N—OR^(C))R³, wherein        -   R^(B) is hydrogen, C₁₋₆alkyl, C₁₋₆haloalkyl,            —C₁₋₆alkyl-R^(B1), —C(O)R³, or —S(O)₂R³, —C(O)(CH₂)₁₋₄COOR,            —C(O)CH(NH₂)(R^(D)), —S(O)₂OR³, —S(O)₂N(R³)₂,            —CH₂—OP(O)₂(OR)₂, or —P(O)(OR³)₂, wherein            -   R^(B1) is cyano, nitro, C₁₋₆alkyl, C₁₋₆haloalkyl, —OR,                —N(R)₂, —SR, —C(O)OR, —C(O)N(R)₂, —C(O)R, —S(O)R,                —S(O)OR, —S(O)N(R)₂, —S(O)₂R, —S(O)₂OR, —S(O)₂N(R)₂,                —OC(O)R, —OC(O)OR, —OC(O)N(R)₂, —N(R)C(O)R, —N(R)C(O)OR,                or —N(R)C(O)N(R)₂;            -   R^(D) is hydrogen, methyl, —CH(CH₃)₂, —CH₂CH(CH₃)₂,                —CH(CH₃)(CH₂CH₃), benzyl, 4-hydroxybenzyl,                —CH₂(3-indolyl), —CH₂SH, —CH₂CH₂SCH₃, —CH₂OH,                —CH(CH₃)OH, —(CH₂)₄—NH₂, —(CH₂)₃—N(H)C(═NH)NH₂,                —CH₂(4-imidazolyl), —CH₂COOH, —CH₂CH₂COOH, —CH₂CONH₂,                —CH₂CH₂CONH₂;        -   each R³ is independently hydrogen, C₁₋₆alkyl, C₁₋₆haloalkyl,            aryl, heteroaryl, C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, 3-10            membered heterocyclyl, arylC₁₋₆alkyl-, heteroarylC₁₋₆alkyl-,            C₃₋₈cycloalkylC₁₋₆alkyl-, C₃₋₈cycloalkenylC₁₋₆alkyl-, or            (3-10 membered heterocyclyl)C₁₋₆alkyl-,        -   wherein            -   the alkyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, 3-10                membered heterocyclyl, C₃₋₈cycloalkylC₁₋₆alkyl-,                C₃₋₈cycloalkenylC₁₋₆alkyl-, and (3-10 membered                heterocyclyl)C₁₋₆alkyl- are each optionally and                independently substituted by one ═R³² group and each                optionally substituted and independently by one, two,                three, or four R³¹ groups;            -   the aryl, heteroaryl, arylC₁₋₆alkyl-, and                heteroarylC₁₋₆alkyl- groups, are each optionally                substituted by one, two, three, or four R³¹ groups;            -   wherein            -   each R³¹ is independently halogen, cyano, nitro,                C₁₋₆alkyl, —C₁₋₆alkyl-R³³, C₁₋₆haloalkyl, —OR, —N(R)₂,                —SR, —C(O)OR, —C(O)N(R)₂, —C(O)R—, —S(O)R, —S(O)OR,                —S(O)N(R)₂, —S(O)₂R, —S(O)₂OR, —S(O)₂N(R)₂, —OC(O)R,                —OC(O)OR, —OC(O)N(R)₂, —N(R)C(O)R, —N(R)C(O)OR,                —N(R)C(O)N(R)₂, wherein                -   R³³ is cyano, —OR, —N(R)₂, —SR, —C(O)OR, —C(O)N(R)₂,                    —C(O)R, —S(O)R, —S(O)OR, —S(O)N(R)₂, —S(O)₂R,                    —S(O)₂OR, —S(O)₂N(R)₂, —OC(O)R, —OC(O)OR,                    —OC(O)N(R)₂, —N(R)C(O)R, —N(R)C(O)OR, or                    —N(R)C(O)N(R)₂;            -   R³² is ═O, ═S, ═N(R), ═N(OR), ═C(R³⁴)₂,                =(spiro-C₃₋₈cycloalkyl), or =(spiro-(3-10 membered                heterocyclyl)), wherein                -   each R³⁴ is independently hydrogen, halogen,                    C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, or 3-10                    membered heterocyclyl;                -   or both R³⁴ taken together with the atom to which                    they are both attached form a monocyclic                    C₃₋₈cycloalkyl or monocyclic 3-8 membered                    heterocyclyl;        -   R^(C) is hydrogen or C₁₋₆alkyl;-   and-   each R is independently hydrogen or R¹⁰, wherein    -   R¹⁰ is C₁₋₆alkyl, C₁₋₆haloalkyl, aryl, heteroaryl,        C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, 3-10 membered heterocyclyl,        arylC₁₋₆alkyl, heteroarylC₁₋₆alkyl-, C₃₋₈cycloalkylC₁₋₆alkyl-,        C₃₋₈cycloalkenylC₁₋₆alkyl-, or (3-10 membered        heterocyclyl)C₁₋₆alkyl-, each R¹⁰ optionally substituted by one,        two, three, or four groups that are each independently halogen,        cyano, nitro, C₁₋₆alkyl, C₁₋₆haloalkyl, —OR¹¹, —N(R¹¹)₂, —SR¹¹,        —C(O)OR¹¹, —C(O)N(R¹¹)₂, —C(O)R¹¹, —S(O)R¹¹, —S(O)OR¹¹,        —S(O)N(R¹¹)₂, —S(O)₂R¹¹, —S(O)₂OR¹¹, —S(O)₂N(R¹¹)₂, —OC(O)R¹¹,        —OC(O)OR¹¹, —OC(O)N(R¹¹)₂, —N(R¹¹)C(O)R¹¹, —N(R¹¹)C(O)OR¹¹,        —N(R¹¹)C(O)N(R¹¹)₂, wherein each R¹¹ is independently hydrogen        or C₁₋₆alkyl.

In one embodiment, the compounds of formula (I) further include thosecompounds where,

-   -   R^(B) is additionally —C(O)N(H)R³ or —C(O)(CH₂)₁₋₄(NR)COOR;    -   R³ is additionally (heteroaryl)-(3-10 membered heterocyclyl)-,    -   R³¹ is additionally —C(O)N(OH)R, —C(N═R¹¹)R, or        —C(N═R¹¹)N(R¹¹)R;    -   R³⁴ is additionally cyano or —C₁₋₆alkyl-OR; and/or    -   R¹⁰ is additionally optionally substituted by —N(R¹¹)S(O)₂R¹¹ or        —C(O)-(3-10 membered heterocyclyl);        such compounds are referred to as compounds of formula (I′).

The invention further comprises subgenera of formula (I) and formula(I′) in which the substituents are selected as any and all combinationsof one or more of structural formula (I), n, R¹, R², R³, R^(A), R^(B),and R^(C), as defined herein, including without limitation, thefollowing:

Structural Formula I is One of Formulae (Ia)-(Ih):

n and R¹ are Selected from One of the Following Groups (1a)-(1u):

-   -   (1a) n is 1, 2, 3, or 4, and each R¹ is as defined for formula        (I).    -   (1b) n is 0, 1, 2, or 3, and each R¹ is as defined for formula        (I).    -   (1c) n is 0, 1, or 2 and each R¹ is as defined for formula (I).    -   (1d) n is 0, 1, or 2 and each R¹ is independently halogen, —OR,        —N(R)₂, or —SR.    -   (1e) n is 0, 1, or 2 and each R¹ is independently halogen, —OR⁰,        —N(R⁰)₂, or —SR⁰, wherein each R⁰ is independently hydrogen or        C₁₋₆alkyl.    -   (1f) n is 0, 1, or 2 and each R¹ is independently fluoro,        chloro, hydroxy, or methoxy.    -   (1g) n is 0, 1, or 2 and each R¹ is independently halogen.    -   (1h) n is 0, 1, or 2 and each R¹ is independently fluoro or        chloro.    -   (1i) n is 0 or 1 and R¹ is as defined for formula (I).    -   (1j) n is 0 or 1 and R¹ is halogen, —OR, —N(R)₂, or —SR.    -   (1k) n is 0 or 1 and R¹ is halogen, —OR⁰, —N(R⁰)₂, or —SR;        wherein each R⁰ is independently hydrogen or C₁₋₆alkyl.    -   (1l) n is 0 or 1 and R¹ is fluoro, chloro, hydroxy, or methoxy.    -   (1m) n is 0 or 1 and R¹ is halogen.    -   (1n) n is 0 or 1 and R¹ is fluoro or chloro.    -   (1o) n is 1 and R¹ is as defined for formula (I).    -   (1p) n is 1 and R¹ is halogen, —OR, —N(R)₂, or —SR;    -   (1q) n is 1 and R¹ is halogen, —OR⁰, —N(R⁰)₂, or —SR⁰; wherein        each R⁰ is independently hydrogen or C₁₋₆alkyl.    -   (1r) n is 1 and R¹ is fluoro, chloro, hydroxy, or methoxy.    -   (1s) n is 1 and R¹ is halogen.    -   (1t) n is 1 and R¹ is fluoro or chloro.    -   (1u) n is 0.

R² is Selected from One of the Following Groups (2a)-(2l):

-   -   (2a) R² is —C₁₋₄alkyl-R^(A).    -   (2b) R² is —C₁₋₂alkyl-R^(A).    -   (2c) R² is —C(H)═C(H)R³.    -   (2d) R² is —C(H)═C(H)R³⁰, wherein R³⁰ is phenyl optionally        substituted by one, two, three, or four R³¹ groups.    -   (2e) R² is —C(H)═C(H)R³⁰, wherein R³⁰ is phenyl optionally        substituted by one or two R³¹ groups.    -   (2f) R² is —CH₂—R^(A), —CH₂CH₂—R^(A), —C(H)(CH₃)CH₂—R^(A), or        —C(H)═C(H)R³.    -   (2 g) R² is —CH₂—R^(A), —CH₂CH₂—R^(A), or —C(H)(CH₃)CH₂—R^(A).    -   (2h) R² is —CH₂—R^(A), —CH₂CH₂—RA, or —C(H)═C(H)R³.    -   (2i) R² is —CH₂—R^(A).    -   (2j) R² is —CH₂CH₂—R^(A).    -   (2k) R² is —C(H)(CH₃)CH₂—R^(A).    -   (2l) R² is —CH₂—R^(A), —CH₂CH₂—R^(A), or —C(H)═C(H)R³.

R^(a) is Selected from One of the Following Groups (3a)-(3n):

-   -   (3a) R^(A) is —CN, —C(O)OR³, or —C(O)N(R³)(R^(C)).    -   (3b) R^(A) is —C(O)R³ or —C(OR^(B))(R³)(R^(C)).    -   (3c) R^(A) is —C(NHR^(B))(R³)(R^(C)), or —C(═N—OR^(C))R³.    -   (3d) R^(A) is —C(NHR^(B))(R³)(R^(C)), wherein R^(B) is hydrogen,        C₁₋₆alkyl, or —C(O)C₁₋₆alkyl.    -   (3e) R^(A) is —C(NH₂)(R³)(R^(C)).    -   (3f) R^(A) is —C(O)OR³.    -   (3 g) R^(A) is —C(O)N(R³)(R^(C)).    -   (3h) R^(A) is —C(O)R³.    -   (3i) R^(A) is —C(OR^(B))(R³)(R^(C)).    -   (3j) R^(A) is —C(OH)(R³)(R^(C)).    -   (3k) R^(A) is —CH(OH)(R³).    -   (3l) R^(A) is —CN, —C(O)R³, —C(O)OR³, —C(O)N(R³)(R^(C)),        —C(OR^(B))(R³)(R), —C(NHR^(B))(R³)(R^(C)), or —C(═N—OR^(C))R³.    -   (3m) R^(A) is —C(O)R³ or —C(OR^(B))(R³)(R^(C)), wherein R^(B) is        hydrogen and R^(C) is hydrogen or C₁₋₆alkyl.    -   (3n) R^(A) is —C(OR^(B))(R³)(R^(C)), wherein R^(B) is hydrogen        and R^(C) is hydrogen or C₁₋₆alkyl.

R^(B) is Selected from One of the Following Groups (4a)-(4k):

-   -   (4a) R^(B) is hydrogen, C₁₋₆alkyl, C₁₋₆haloalkyl,        —C₁₋₆alkyl-R^(B)1, —C(O)(CH₂)₁₋₄COOR^(B2), —C(O)C(NH₂)R^(D),        —P(O₃)(R^(B2))₂, —CH₂—OP(O)₂(OR)₂, wherein R^(D) is the side        chain of natural alpha amino acids, —C(O)R³, or —S(O)₂R³,        wherein R^(B1) is cyano, nitro, C₁₋₆alkyl, C₁₋₆haloalkyl,        —OR^(B2), —N(R^(B2))₂, —SR^(B2), —C(O)OR^(B2), —C(O)N(R^(B2))₂,        —C(O)R^(B2), —S(O)R^(B2), —S(O)OR^(B2), —S(O)N(R^(B2))₂,        —S(O)₂R^(B2), —S(O)₂OR^(B2), —S(O)₂N(R^(B2))₂, —OC(O)R^(B2),        —OC(O)OR^(B2), —OC(O)N(R^(B2))₂, —N(R^(B2))C(O)R^(B2),        —N(R^(B2))C(O)OR², or —N(R^(B2))C(O)N(R^(B2))₂, wherein each        R^(B2) is independently hydrogen or C₁₋₆alkyl.    -   (4b) R^(B) is hydrogen, C₁₋₆alkyl, C₁₋₆haloalkyl,        —C₁₋₆alkyl-R¹¹, —C(O)R³, or —S(O)₂R³, wherein R^(B)1 is cyano,        nitro, C₁₋₆alkyl, C₁₋₆haloalkyl, —OR^(B2), —N(R^(B2))₂,        —SR^(B2), —C(O)OR^(B2), —C(O)N(R^(B2))₂, —C(O)R^(B2),        —S(O)R^(B2), —S(O)OR^(B2), —S(O)N(R^(B2))₂, —S(O)₂R^(B2),        —S(O)₂OR^(B2), —S(O)₂N(R^(B2))₂, —OC(O)R^(B2), —OC(O)OR^(B2),        —OC(O)N(R^(B2))₂, —N(R^(B2))C(O)R^(B2), —N(R^(B2))C(O)OR, or        —N(R^(B2))C(O)N(R^(B2))₂, wherein each R^(B2) is independently        hydrogen or C₁₋₆alkyl.    -   (4c) R^(B) is hydrogen, C₁₋₆alkyl, C₁₋₆haloalkyl, or        —C₁₋₆alkyl-R^(B1), wherein R^(B1) is cyano, nitro, C₁₋₆alkyl,        C₁₋₆haloalkyl, —OR^(B2), —N(R^(B))₂, —SR^(B2), —C(O)OR^(B2),        —C(O)N(R^(B2))₂, —C(O)R^(B2), —S(O)R^(B2), —S(O)OR^(B2),        —S(O)N(R^(B2))₂, —S(O)₂R^(B2), —S(O)₂OR^(B2), —S(O)₂N(R^(B2))₂,        —OC(O)R^(B2), —OC(O)OR^(B2), —OC(O)N(R²)₂, —N(R^(B2))C(O)R^(B2),        —N(R^(B2))C(O)OR^(B2), or —N(R²)C(O)N(R^(B2))₂, wherein each        R^(B2) is independently hydrogen or C₁₋₆alkyl.    -   (4d) R^(B) is hydrogen, C₁₋₆alkyl, C₁₋₆haloalkyl, or        —C₁₋₆alkyl-R^(B1), wherein R^(B1) is cyano, —C(O)OR^(B2),        —C(O)N(R²)₂, —C(O)R^(B2), —S(O)₂R^(B2), —S(O)₂OR², or        —S(O)₂N(R^(B2))₂, wherein each R^(B2) is independently hydrogen        or C₁₋₆alkyl.    -   (4e) R^(B) is —C₁₋₆alkyl-R^(B1), wherein R^(B1) is cyano,        —C(O)OR^(B2), —C(O)N(R^(B2))₂, —C(O)R², —S(O)₂R^(B2),        —S(O)₂OR^(B2), or —S(O)₂N(R^(B2))₂, wherein each R^(B2) is        independently hydrogen or C₁₋₆alkyl.    -   (4f) R^(B) is hydrogen, C₁₋₆alkyl, C₁₋₆haloalkyl,        —C₁₋₆alkyl-R^(B1), —C(O)R^(B2), or —S(O)₂R^(B2), wherein R^(B1)        is —C(O)OR^(B3), —C(O)N(R^(B3))₂, —S(O)₂OR^(B3), or        —S(O)₂N(R³)₂, R^(B2) is C₁₋₆ alkyl; and R^(B3) is hydrogen or        C₁₋₆alkyl.    -   (4g) R^(B) is hydrogen, C₁₋₆alkyl, or C₁₋₆haloalkyl.    -   (4h) R^(B) is hydrogen or C₁₋₆alkyl;    -   (4i) R^(B) is hydrogen.    -   (4j) R^(B) is C₁₋₆alkyl.    -   (4k) R^(B) is hydrogen, —C(O)R¹², —C(O)(CH₂)₁₋₄COOR^(B2),        —C(O)C(NH₂)RD, —P(O)(OR^(B2))₂, —CH₂—OP(O)₂(OR)₂, —S(O)₂R^(B2),        —C(O)N(R^(B2))₂, —S(O)₂OR^(B2), —S(O)₂N(R³)₂, wherein and R^(B2)        is hydrogen or C₁₋₆alkyl.

R^(C) is Selected from One of the Following Groups (5a)-(5g):

-   -   (5a) R^(C) is hydrogen or C₁₋₄alkyl.    -   (5b) R^(C) is hydrogen or C₁₋₂alkyl.    -   (5c) R^(C) is hydrogen or methyl.    -   (5d) R^(C) is hydrogen.    -   (5e) R^(C) is C₁₋₆alkyl.    -   (5f) R^(C) is C₁₋₄alkyl.    -   (5g) R^(C) is methyl.

R³ is Selected from One of the Following Groups (6a)-(6z):

-   -   (6a) R³ is hydrogen, C₁₋₆alkyl, aryl, heteroaryl,        C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, 3-10 membered heterocyclyl, or        C₃₋₈cycloalkylC₁₋₆alkyl-, wherein the C₁₋₆alkyl, C₃₋₈cycloalkyl,        C₃₋₈cycloalkenyl, 3-10 membered heterocyclyl, and        C₃₋₈cycloalkylC₁₋₆alkyl-, are each optionally substituted by one        ═R³² group and one or two R³¹ groups; and the aryl and        heteroaryl groups, are each optionally substituted by one or two        R³¹ groups.    -   (6b) R³ is aryl, heteroaryl, C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl,        3-10 membered heterocyclyl, or C₃₋₈cycloalkylC₁₋₆alkyl-, wherein        the C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, 3-10 membered        heterocyclyl, and C₃₋₈cycloalkylC₁₋₆alkyl-, are each optionally        and independently substituted by one ═R³² group and each        optionally and independently substituted by one or two R³¹        groups; and the aryl and heteroaryl groups, are each optionally        substituted by one or two R³¹ groups.    -   (6c) R³ is phenyl, a five or six membered heteroaryl, monocyclic        C₅₋₈cycloalkyl, monocyclic C₅₋₈cycloalkenyl, a five or six        membered monocyclic heterocyclyl, or (monocyclic        C₅₋₈cycloalkyl)C₁₋₆ alkyl-, wherein the C₅₋₈cycloalkyl,        C₅₋₈cycloalkenyl, 5-6 membered heterocyclyl, and        C₅₋₈cycloalkylC₁₋₆alkyl-, are each optionally and independently        substituted by one ═R³² group and each optionally and        independently substituted by one or two R³¹ groups; and the        phenyl and heteroaryl groups, are each optionally substituted by        one or two R³¹ groups.    -   (6d) R³ is phenyl or a five or six membered heteroaryl, each        optionally substituted by one or two R³¹ groups.    -   (6e) R³ is monocyclic C₅₋₈cycloalkyl, monocyclic        C₅₋₈cycloalkenyl, a five or six membered monocyclic        heterocyclyl, or (monocyclic C₅₋₈cycloalkyl)C₁₋₆alkyl-, each        optionally substituted by one ═R³² group and one or two R³¹        groups.    -   (6f) R³ is

wherein bond a is a single bond or a double bond;

-   -    m is 0, 1, or 2;    -    p is 0 or 1; and wherein        -   when bond a is a single bond, then Z is —C(R³⁶)₂—,            —C(═R³²)—, —N(R³⁵)—, or —O—, wherein each R³⁶ is            independently hydrogen or R³¹; and        -   R³⁵ is hydrogen, C₁₋₆alkyl, —C(O)R, —S(O)₂R, —C(O)OR,            —C(O)N(R)₂, —S(O)₂OR, or —S(O)₂N(R)₂;        -   and when bond a is a double bond, then Z is —C(R³⁶)═ or —N═.    -   (6g) R³ is

wherein bond a is a single bond or a double bond;

-   -    m is 0, 1, or 2;    -    p is 0 or 1; and wherein        -   when bond a is a single bond, then Z is —C(R³⁶)₂—,            —C(═R³²)—, —N(R³⁵)—, or —O—, wherein each R³⁶ is            independently hydrogen or R³¹; and        -   R³⁵ is hydrogen, C₁₋₆alkyl, —C(O)R, —S(O)₂R, —C(O)OR,            —C(O)N(R)₂, —S(O)₂OR, or —S(O)₂N(R)₂;        -   and when bond a is a double bond, then Z is —C(R³⁶)═ or —N═.    -   (6h) As group (6g), wherein when bond a is a single bond, then Z        is —C(R³⁶)₂— or —C(═R³²)—; and when bond a is a double bond,        then Z is —C(R³⁶)═ or —N═.    -   (6i) As group (6g), wherein m is 0; when bond a is a single        bond, then Z is —C(R³⁶)₂— or —C(═R³²)—; and when bond a is a        double bond, then Z is —C(R³⁶)═ or —N═.    -   (6j) As group (6g), wherein bond a is a single bond; and Z is        —C(R³⁶)₂— or —C(═R³²)—.    -   (6k) As group (6g), wherein bond a is a single bond; and Z is        —C(R³⁶)₂—.    -   (6l) As group (6g), wherein bond a is a single bond; and Z is        —C(═R³²—.    -   (6m) As group (6g), wherein m is 0; bond a is a single bond; and        Z is —C(R³⁶)₂— or —C(═R³²)—.    -   (6n) As group (6g), wherein m is 0; bond a is a single bond; and        Z is —C(R³⁶)₂—.    -   (6o) As group (6g), wherein m is 0; bond a is a single bond; and        Z is —C(═R³²)—.    -   (6p) As group (6g), wherein bond a is a single bond; and Z is        —C(R³⁶)₂— or —C(═R³²)—, wherein each R³⁶ is independently        hydrogen, halogen, C₁₋₆alkyl, —C₁₋₆alkyl-OH, C₁₋₆haloalkyl, or        —OH, wherein        -   R³² is ═O, ═C(R³⁴)₂, =(spiro-C₃₋₈cycloalkyl), or            =(spiro-(3-8 membered heterocyclyl)), wherein each R³⁴ is            independently hydrogen, halogen, C₁₋₆alkyl, C₁₋₆haloalkyl,            C₃₋₈cycloalkyl, or 3-8 membered heterocyclyl.    -   (6q) As group (6g), wherein m is 0; bond a is a single bond; and        Z is —C(R³⁶)₂— or —C(═R³²)—, wherein each R³⁶ is independently        hydrogen, halogen, C₁₋₆alkyl, —C₁₋₆alkyl-OH, C₁₋₆haloalkyl, or        —OH, wherein        -   R³² is ═O, ═C(R³⁴)₂, =(spiro-C₃₋₈cycloalkyl), or            =(spiro-(3-8 membered heterocyclyl)), wherein each R³⁴ is            independently hydrogen, halogen, C₁₋₆alkyl, C₁₋₆haloalkyl,            C₃₋₈cycloalkyl, or 3-8 membered heterocyclyl.    -   (6r) As group (6g), wherein bond a is a single bond; and Z is        —N(R³⁵)— or —O—.    -   (6s) R³ is hydrogen, C₁₋₆alkyl, aryl, heteroaryl,        C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, 3-10 membered heterocyclyl, or        C₃₋₈cycloalkylC₁₋₆alkyl, wherein        -   the C₁₋₆alkyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, 3-10            membered heterocyclyl, and C₃₋₈cycloalkylC₁₋₆alkyl, are each            optionally substituted by one ═R³² group and one or two R³¹            groups;        -   the aryl and heteroaryl groups, are each optionally            substituted by one or two R³¹ groups; wherein        -   each R³¹ is independently halogen, cyano, nitro, C₁₋₆alkyl,            —C₁₋₆alkyl-R³³, C₁₋₆haloalkyl, —OR, —N(R)₂, —SR, —C(O)OR,            —C(O)N(R)₂, —C(O)R, —S(O)R, —S(O)OR, —S(O)N(R)₂, —S(O)₂R,            —S(O)₂OR, —S(O)₂N(R)₂, —OC(O)R, —OC(O)OR, —OC(O)N(R)₂,            —N(R)C(O)R, —N(R)C(O)OR, —N(R)C(O)N(R)₂, wherein R³³ is —OR,            —N(R)₂, or —SR; and        -   R³² is oxo, ═C(R³⁴)₂, =(spiro-C₃₋₈cycloalkyl), or            =(spiro-(3-10 membered heterocyclyl)), wherein each R³⁴ is            independently hydrogen, halogen, C₁₋₆alkyl, or            C₃₋₈cycloalkyl.    -   (6t) R³ is hydrogen, C₁₋₆alkyl, aryl, heteroaryl,        C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, 3-10 membered heterocyclyl, or        C₃₋₈cycloalkylC₁₋₆alkyl-, wherein        -   the C₁₋₆alkyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, 3-10            membered heterocyclyl, and C₃₋₈cycloalkylC₁₋₆alkyl-, are            each optionally and independently substituted by one ═R³²            group and each optionally and independently substituted by            one or two R³¹ groups;        -   the aryl and heteroaryl groups, are each optionally            substituted by one or two R³¹ groups;        -   wherein            -   each R³¹ is independently halogen, cyano, nitro,                C₁₋₆alkyl, —C₁₋₆alkyl-R³³, C₁₋₆haloalkyl, —OR, —N(R)₂,                —SR, —C(O)OR, —C(O)N(R)₂, —C(O)R, —S(O)R, —S(O)OR,                —S(O)N(R)₂, —S(O)₂R, —S(O)₂OR, —S(O)₂N(R)₂, —OC(O)R,                —OC(O)OR, —OC(O)N(R)₂, —N(R)C(O)R, —N(R)C(O)OR,                —N(R)C(O)N(R)₂, wherein R³³ is —OR, —N(R)₂, or —SR;            -   and            -   R³² is oxo, ═C(R³⁴)₂, =(spiro-C₃₋₈cycloalkyl), or                =(spiro-(3-10 membered heterocyclyl)), wherein each R³⁴                is independently hydrogen, halogen, C₁₋₆alkyl, or                C₃₋₈cycloalkyl.    -   (6u) R³ is aryl, heteroaryl, C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl,        or 3-10 membered heterocyclyl, wherein the C₃₋₈cycloalkyl,        C₃₋₈cycloalkenyl, and 3-10 membered heterocyclyl are each        optionally substituted by one ═R³² group and one, two, three, or        four R³¹ groups; and        -   the aryl and heteroaryl are each optionally substituted by            one, two, three, or four R³¹ groups.    -   (6v) R³ is phenyl, cyclopentyl, cyclohexyl, cyclohexenyl,        furanyl, tetrahydropyranyl, piperidinyl, imidazolyl, thiazolyl,        each optionally substituted by one, two, three, or four R³¹        groups, and wherein the cyclopentyl, cyclohexyl, cyclohexenyl,        andy piperidinyl groups are each optionally substituted by one        ═R³² group.    -   (6w) R³ is phenyl, cyclopentyl, cyclohexyl, cyclohex-1-en-1-yl,        cyclohex-3-en-1-yl, furan-2-yl, furan-3-yl,        tetrahydropyran-3-yl, tetrahydropyran-4-yl, piperidin-3-yl,        piperidin-4-yl, imidazol-2-yl, imidazol-4-yl, thiazol-2-yl,        thiazol-4-yl, thiazol-5-yl, each optionally substituted by one        or two R³¹ groups, and wherein the cyclopentyl, cyclohexyl,        cyclohexenyl, andy piperidinyl groups are each optionally        substituted by one ═R³² group.    -   (6x) Any one of groups (6a)-(6w), wherein each R is        independently hydrogen, C₁₋₆alkyl, C₁₋₆haloalkyl, aryl,        heteroaryl, C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, 3-10 membered        heterocyclyl, arylC₁₋₆alkyl, heteroarylC₁₋₆alkyl-,        C₃₋₈cycloalkylC₁₋₆alkyl-, C₃₋₈cycloalkenylC₁₋₆alkyl-, or (3-10        membered heterocyclyl)C₁₋₆alkyl-.    -   (6y) Any one of groups (6a)-(6w), wherein each R is        independently hydrogen, C₁₋₆alkyl, C₁₋₆haloalkyl, phenyl, 5- or        6-membered heteroaryl, C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, 3-8        membered heterocyclyl, benzyl, (5- or 6-membered        heteroaryl)C₁₋₆alkyl-, C₃₋₈ cycloalkylC₁₋₆alkyl-,        C₃₋₈cycloalkenylC₁₋₆alkyl-, or (3-8 membered        heterocyclyl)C₁₋₆alkyl-.    -   (6z) Any one of groups (6a)-(6w), wherein each R is        independently hydrogen or C₁₋₆alkyl.

Particular embodiments of this aspect of the invention include compoundsof any one of the formulae (I), (I′), and (Ia)-(Id), each as defined ineach of the following rows, wherein each entry is a group number asdefined above (e.g., (is) refers to n is 1 and each R¹ is halogen), anda dash “-” indicates that the variable is as defined for formula (I) or(I′) or defined according to any one of the applicable variabledefinitions (1a)-(6z) [e.g., when R^(C) is a dash, it can be either asdefined for Formula (I) or (I′) or any one of definitions (5a)-(5g)]:

n & R¹ R² R^(A) R³ (1)-1 1e 2b 3h 6c (1)-2 1f 2b 3h 6c (1)-3 1k 2b 3h 6c(1)-4 1l 2b 3h 6c (1)-5 1m 2b 3h 6c (1)-6 1n 2b 3h 6c (1)-7 1u 2b 3h 6c(1)-8 1e 2b 3h 6f (1)-9 1f 2b 3h 6f (1)-10 1k 2b 3h 6f (1)-11 1l 2b 3h6f (1)-12 1m 2b 3h 6f (1)-13 1n 2b 3h 6f (1)-14 1u 2b 3h 6f (1)-15 1e 2b3h 6y (1)-16 1f 2b 3h 6y (1)-17 1k 2b 3h 6y (1)-18 1l 2b 3h 6y (1)-19 1m2b 3h 6y (1)-20 1n 2b 3h 6y (1)-21 1u 2b 3h 6y (1)-22 1e 2b 3i 6c (1)-231f 2b 3i 6c (1)-24 1k 2b 3i 6c (1)-25 1l 2b 3i 6c (1)-26 1m 2b 3i 6c(1)-27 1n 2b 3i 6c (1)-28 1u 2b 3i 6c (1)-29 1e 2b 3i 6f (1)-30 1f 2b 3i6f (1)-31 1k 2b 3i 6f (1)-32 1l 2b 3i 6f (1)-33 1m 2b 3i 6f (1)-34 1n 2b3i 6f (1)-35 1u 2b 3i 6f (1)-36 1e 2b 3i 6y (1)-37 1f 2b 3i 6y (1)-38 1k2b 3i 6y (1)-39 1l 2b 3i 6y (1)-40 1m 2b 3i 6y (1)-41 1n 2b 3i 6y (1)-421u 2b 3i 6y (1)-43 1e 2b 3k 6c (1)-44 1f 2b 3k 6c (1)-45 1k 2b 3k 6c(1)-46 1l 2b 3k 6c (1)-47 1m 2b 3k 6c (1)-48 1n 2b 3k 6c (1)-49 1u 2b 3k6c (1)-50 1e 2b 3k 6f (1)-51 1f 2b 3k 6f (1)-52 1k 2b 3k 6f (1)-53 1l 2b3k 6f (1)-54 1m 2b 3k 6f (1)-55 1n 2b 3k 6f (1)-56 1u 2b 3k 6f (1)-57 1e2b 3k 6y (1)-58 1f 2b 3k 6y (1)-59 1k 2b 3k 6y (1)-60 1l 2b 3k 6y (1)-611m 2b 3k 6y (1)-62 1n 2b 3k 6y (1)-63 1u 2b 3k 6y (1)-64 1e 2i 3h 6c(1)-65 1f 2i 3h 6c (1)-66 1k 2i 3h 6c (1)-67 1l 2i 3h 6c (1)-68 1m 2i 3h6c (1)-69 1n 2i 3h 6c (1)-70 1u 2i 3h 6c (1)-71 1e 2i 3h 6f (1)-72 1f 2i3h 6f (1)-73 1k 2i 3h 6f (1)-74 1l 2i 3h 6f (1)-75 1m 2i 3h 6f (1)-76 1n2i 3h 6f (1)-77 1u 2i 3h 6f (1)-78 1e 2i 3h 6y (1)-79 1f 2i 3h 6y (1)-801k 2i 3h 6y (1)-81 1l 2i 3h 6y (1)-82 1m 2i 3h 6y (1)-83 1n 2i 3h 6y(1)-84 1u 2i 3h 6y (1)-85 1e 2i 3i 6c (1)-86 1f 2i 3i 6c (1)-87 1k 2i 3i6c (1)-88 1l 2i 3i 6c (1)-89 1m 2i 3i 6c (1)-90 1n 2i 3i 6c (1)-91 1u 2i3i 6c (1)-92 1e 2i 3i 6f (1)-93 1f 2i 3i 6f (1)-94 1k 2i 3i 6f (1)-95 1l2i 3i 6f (1)-96 1m 2i 3i 6f (1)-97 1n 2i 3i 6f (1)-98 1u 2i 3i 6f (1)-991e 2i 3i 6y (1)-100 1f 2i 3i 6y (1)-101 1k 2i 3i 6y (1)-102 1l 2i 3i 6y(1)-103 1m 2i 3i 6y (1)-104 1n 2i 3i 6y (1)-105 1u 2i 3i 6y (1)-106 1e2i 3k 6c (1)-107 1f 2i 3k 6c (1)-108 1k 2i 3k 6c (1)-109 1l 2i 3k 6c(1)-110 1m 2i 3k 6c (1)-111 1n 2i 3k 6c (1)-112 1u 2i 3k 6c (1)-113 1e2i 3k 6f (1)-114 1f 2i 3k 6f (1)-115 1k 2i 3k 6f (1)-116 1l 2i 3k 6f(1)-117 1m 2i 3k 6f (1)-118 1n 2i 3k 6f (1)-119 1u 2i 3k 6f (1)-120 1e2i 3k 6y (1)-121 1f 2i 3k 6y (1)-122 1k 2i 3k 6y (1)-123 1l 2i 3k 6y(1)-124 1m 2i 3k 6y (1)-125 1n 2i 3k 6y (1)-126 1u 2i 3k 6y (1)-127 1e2j 3h 6c (1)-128 1f 2j 3h 6c (1)-129 1k 2j 3h 6c (1)-130 1l 2j 3h 6c(1)-131 1m 2j 3h 6c (1)-132 1n 2j 3h 6c (1)-133 1u 2j 3h 6c (1)-434 1e2j 3h 6f (1)-135 1f 2j 3h 6f (1)-136 1k 2j 3h 6f (1)-137 1l 2j 3h 6f(1)-138 1m 2j 3h 6f (1)-139 1n 2j 3h 6f (1)-140 1u 2j 3h 6f (1)-141 1e2j 3h 6y (1)-142 1f 2j 3h 6y (1)-143 1k 2j 3h 6y (1)-144 1l 2j 3h 6y(1)-145 1m 2j 3h 6y (1)-146 1n 2j 3h 6y (1)-147 1u 2j 3h 6y (1)-148 1e2j 3i 6c (1)-149 1f 2j 3i 6c (1)-150 1k 2j 3i 6c (1)-151 1l 2j 3i 6c(1)-152 1m 2j 3i 6c (1)-153 1n 2j 3i 6c (1)-154 1u 2j 3i 6c (1)-155 1e2j 3i 6f (1)-156 1f 2j 3i 6f (1)-157 1k 2j 3i 6f (1)-158 1l 2j 3i 6f(1)-159 1m 2j 3i 6f (1)-160 1n 2j 3i 6f (1)-161 1u 2j 3i 6f (1)-162 1e2j 3i 6y (1)-163 1f 2j 3i 6y (1)-164 1k 2j 3i 6y (1)-165 1l 2j 3i 6y(1)-166 1m 2j 3i 6y (1)-167 1n 2j 3i 6y (1)-168 1u 2j 3i 6y (1)-169 1e2j 3k 6c (1)-170 1f 2j 3k 6c (1)-171 1k 2j 3k 6c (1)-172 1l 2j 3k 6c(1)-173 1m 2j 3k 6c (1)-174 1n 2j 3k 6c (1)-175 1u 2j 3k 6c (1)-176 1e2j 3k 6f (1)-177 1f 2j 3k 6f (1)-178 1k 2j 3k 6f (1)-179 1l 2j 3k 6f(1)-180 1m 2j 3k 6f (1)-181 1n 2j 3k 6f (1)-182 1u 2j 3k 6f (1)-183 1e2j 3k 6y (1)-184 1f 2j 3k 6y (1)-185 1k 2j 3k 6y (1)-186 1l 2j 3k 6y(1)-187 1m 2j 3k 6y (1)-188 1n 2j 3k 6y (1)-189 1u 2j 3k 6y (1)-190 1e2b — — (1)-191 1f 2b — — (1)-192 1k 2b — — (1)-193 1l 2b — — (1)-194 1m2b — — (1)-195 1n 2b — — (1)-196 1u 2b — — (1)-197 1e 2c — — (1)-198 1f2c — — (1)-199 1k 2c — — (1)-200 1l 2c — — (1)-201 1m 2c — — (1)-202 1n2c — — (1)-203 1u 2c — — (1)-204 1e 2i — — (1)-205 1f 2i — — (1)-206 1k2i — — (1)-207 1l 2i — — (1)-208 1m 2i — — (1)-209 1n 2i — — (1)-210 1u2i — — (1)-211 1e 2j — — (1)-212 1f 2j — — (1)-213 1k 2j — — (1)-214 1l2j — — (1)-215 1m 2j — — (1)-216 1n 2j — — (1)-217 1u 2j — — (1)-218 1e2c — 6c (1)-219 1f 2c — 6c (1)-220 1k 2c — 6c (1)-221 1l 2c — 6c (1)-2221m 2c — 6c (1)-223 1n 2c — 6c (1)-224 1u 2c — 6c (1)-225 1e 2c — 6f(1)-226 1f 2c — 6f (1)-227 1k 2c — 6f (1)-228 1l 2c — 6f (1)-229 1m 2c —6f (1)-230 1n 2c — 6f (1)-231 1u 2c — 6f (1)-232 1e 2c — 6y (1)-233 1f2c — 6y (1)-234 1k 2c — 6y (1)-235 1l 2c — 6y (1)-236 1m 2c — 6y (1)-2371n 2c — 6y (1)-238 1u 2c — 6y (1)-239 — 2b 3h — (1)-240 — 2b 3i —(1)-241 — 2b 3k — (1)-242 — 2i 3h — (1)-243 — 2i 3i — (1)-244 — 2i 3k —(1)-245 — 2j 3h — (1)-246 — 2j 3i — (1)-247 — 2j 3k — (1)-248 — 2b 3h 6c(1)-249 — 2b 3i 6f (1)-250 — 2b 3k 6c (1)-251 — 2i 3h 6f (1)-252 — 2i 3i6y (1)-253 — 2i 3k 6c (1)-254 — 2j 3h 6f (1)-255 — 2j 3i 6y (1)-256 — 2j3k 6c (1)-257 — 2b 3h 6f (1)-258 — 2b 3i 6y (1)-259 — 2b 3k 6c (1)-260 —2i 3h 6f (1)-261 — 2i 3i 6y (1)-262 — 2i 3k 6c (1)-263 — 2j 3h 6f(1)-264 — 2j 3i 6y (1)-265 — 2j 3k 6c (1)-266 — 2b 3h 6f (1)-267 — 2b 3i6y (1)-268 — 2b 3k 6c (1)-269 — 2i 3h 6f (1)-270 — 2i 3i 6y (1)-271 — 2i3k 6c (1)-272 — 2j 3h 6f (1)-273 — 2j 3i 6y (1)-274 — 2j 3k 6c

In another aspect, the invention provides the compound according toformula (II),

-   -   or a pharmaceutically acceptable salt thereof, wherein    -   n is 0 or 1;    -   each R¹ is independently halogen, —OR, —N(R)₂, or —SR;    -   each R³ is independently hydrogen, C₁₋₆alkyl, aryl, heteroaryl,        C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, 3-10 membered heterocyclyl, or        C₃₋₈cycloalkylC₁₋₆alkyl-, wherein        -   the C₁₋₆alkyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, 3-10            membered heterocyclyl, and C₃₋₈cycloalkylC₁₋₆alkyl-, are            each optionally and independently substituted by one ═R³²            group and each optionally and independently substituted by            one or two R³¹ groups;        -   the aryl and heteroaryl groups, are each optionally            substituted by one or two R³¹ groups; wherein            -   each R³¹ is independently halogen, cyano, nitro,                C₁₋₆alkyl, —C₁₋₆alkyl-R³³, C₁₋₆haloalkyl, —OR, —N(R)₂,                —SR, —C(O)OR, —C(O)N(R)₂, —C(O)R, —S(O)R, —S(O)OR,                —S(O)N(R)₂, —S(O)₂R, —S(O)₂OR, —S(O)₂N(R)₂, —OC(O)R,                —OC(O)OR, —OC(O)N(R)₂, —N(R)C(O)R, —N(R)C(O)OR,                —N(R)C(O)N(R)₂, wherein R³³ is —OR, —N(R)₂, or —SR;            -   R³² is oxo, ═C(R³⁴)₂, =(spiro-C₃₋₈cycloalkyl), or                =(spiro-(3-10 membered heterocyclyl)), wherein each R³⁴                is independently hydrogen, halogen, C₁₋₆alkyl, or                C₃₋₈cycloalkyl; and    -   R^(C) is hydrogen or C₁₋₆alkyl; and

-   each R is independently hydrogen or R¹⁰, wherein    -   R¹⁰ is C₁₋₆alkyl, C₁₋₆haloalkyl, aryl, heteroaryl,        C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, 3-10 membered heterocyclyl,        arylC₁₋₆alkyl, heteroarylC₁₋₆alkyl-, C₃₋₈cycloalkylC₁₋₆alkyl-,        C₃₋₈cycloalkenylC₁₋₆alkyl-, or (3-10 membered        heterocyclyl)C₁₋₆alkyl-, each R¹⁰ optionally substituted by one,        two, three, or four groups that are each independently halogen,        cyano, nitro, C₁₋₆alkyl, C₁₋₆haloalkyl, —OR¹¹, —N(R¹¹)₂, —SR¹¹,        —C(O)OR¹¹, —C(O)N(R¹¹)₂, —C(O)R¹¹, —S(O)R¹¹, —S(O)OR¹¹,        —S(O)N(R¹¹)₂, —S(O)₂R¹¹, —S(O)₂OR¹, —S(O)₂N(R¹¹)₂, —OC(O)R¹¹,        —OC(O)OR¹, —OC(O)N(R¹¹)₂, —N(R¹¹)C(O)R¹¹, —N(R¹¹)C(O)OR¹¹,        —N(R¹¹)C(O)N(R¹¹)₂, wherein each R¹¹ is independently hydrogen        or C₁₋₆alkyl.

In one embodiment, the compounds of formula (II) further include thosecompounds where,

-   -   R³ is additionally (heteroaryl)-(3-10 membered heterocyclyl)-;    -   R³¹ is additionally —C(O)N(OH)R, —C(N═R¹¹)R, or        —C(N═R¹¹)N(R¹¹)R;    -   R³⁴ is additionally cyano or —C₁₋₆alkyl-OR; and/or    -   R¹⁰ is additionally optionally substituted by —N(R¹¹)S(O)₂R¹¹ or        —C(O)-(3-10 membered heterocyclyl);        such compounds are referred to as compounds of formula (II′).

The invention further comprises subgenera of formula (II) or (II′) inwhich the substituents are selected as any and all combinations of oneor more of structural formula (II), n, R¹, R³, and R^(C) as definedherein, including without limitation, the following:

Structural Formula II is One of Formulae (IIa)-(IId):

(IIa): wherein the stereoisomeric configuration of carbon-1 (C-1) andcarbon-3 (C-3) of formula (II) are respectively (R, R).

(IIb): wherein the stereoisomeric configuration of carbon-1 and carbon-3are of formula (II) respectively (R, S).

(IIc): wherein the stereoisomeric configuration of carbon-1 and carbon-3are of formula (II) respectively (S, R).

(IId): wherein the stereoisomeric configuration of carbon-1 and carbon-3are of formula (II) respectively (S, S).

Structural Formula II is One of Formulae (IIe)-(IIh):

(IIe): wherein the stereoisomeric configuration of carbon-1 (C-1) andcarbon-3 (C-3) of formula (II) are respectively (R, R).

(IIf): wherein the stereoisomeric configuration of carbon-1 and carbon-3are of formula (II) respectively (R, S).

(IIg): wherein the stereoisomeric configuration of carbon-1 and carbon-3are of formula (II) respectively (S, R).

(IIh): wherein the stereoisomeric configuration of carbon-1 and carbon-3are of formula (II) respectively (S, S).

n and R¹ are selected from one of the following groups (7a)-(7i):

-   -   (7a) n is 0 or 1 and R¹ is halogen, —OR⁰, —N(R⁰)₂, or —SR⁰;        wherein each R⁰ is independently hydrogen or C₁₋₆alkyl.    -   (7b) n is 0 or 1 and R¹ is fluoro, chloro, hydroxy, or methoxy.    -   (7c) n is 0 or 1 and R¹ is halogen.    -   (7d) n is 0 or 1 and R¹ is fluoro or chloro.    -   (7e) n is 1 and R¹ is halogen, —OR⁰, —N(R⁰)₂, or —SR; wherein        each R⁰ is independently hydrogen or C₁₋₆alkyl.    -   (7f) n is 1 and R¹ is fluoro, chloro, hydroxy, or methoxy.    -   (7 g) n is 1 and R¹ is halogen.    -   (7h) n is 1 and R¹ is fluoro or chloro.    -   (7i) n is 0.

R^(C) is Selected from One of the Following Groups (8a)-(8):

-   -   (8a) R^(C) is hydrogen or C₁₋₄alkyl.    -   (8b) R^(C) is hydrogen or C₁₋₂alkyl.    -   (8c) R^(C) is hydrogen or methyl.    -   (8d) R^(C) is hydrogen.    -   (8e) R^(C) is C₁₋₆alkyl.    -   (8f) R^(C) is C₁₋₄alkyl.    -   (8g) R^(C) is methyl.

R³ is Selected from One of the Following Groups (9a)-(9x):

-   -   (9a) R³ is aryl, heteroaryl, C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl,        3-10 membered heterocyclyl, or C₃₋₈cycloalkylC₁₋₆alkyl-, wherein        the C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, 3-10 membered        heterocyclyl, and C₃₋₈cycloalkylC₁₋₆ alkyl-, are each optionally        and independently substituted by one ═R³² group and each        optionally and independently substituted by one or two R³¹        groups; and the aryl and heteroaryl groups, are each optionally        substituted by one or two R³¹ groups.    -   (9b) R³ is phenyl, a five or six membered heteroaryl, monocyclic        C₅₋₈cycloalkyl, monocyclic C₅₋₈cycloalkenyl, a five or six        membered monocyclic heterocyclyl, or (monocyclic        C₅₋₈cycloalkyl)C₁₋₆alkyl-, wherein the C₅₋₈cycloalkyl,        C₅₋₈cycloalkenyl, 5-6 membered heterocyclyl, and        C₅₋₈cycloalkylC₁₋₆ alkyl-, are each optionally and independently        substituted by one ═R³² group and each optionally and        independently substituted by one or two R³¹ groups; and the        phenyl and heteroaryl groups, are each optionally substituted by        one or two R³¹ groups.    -   (9c) R³ is phenyl or a five or six membered heteroaryl, each        optionally substituted by one or two R³¹ groups.    -   (9d) R³ is monocyclic C₅₋₈cycloalkyl, monocyclic        C₅₋₈cycloalkenyl, a five or six membered monocyclic        heterocyclyl, or (monocyclic C₅₋₈cycloalkyl)C₁₋₆alkyl-, each        optionally substituted by one ═R³² group and one or two R³¹        groups.    -   (9e) R³ is

wherein bond a is a single bond or a double bond;

-   -    m is 0, 1, or 2;    -    p is 0 or 1; and wherein        -   when bond a is a single bond, then Z is —C(R³⁶)₂—,            —C(═R³²)—, —N(R³⁵)—, or —O—, wherein each R³⁶ is            independently hydrogen or R³¹; and        -   R³⁵ is hydrogen, C₁₋₆alkyl, —C(O)R, —S(O)₂R, —C(O)OR,            —C(O)N(R)₂, —S(O)₂OR, or —S(O)₂N(R)₂;        -   and when bond a is a double bond, then Z is —C(R³⁶)═ or —N═.    -   (9) R³ is

wherein bond a is a single bond or a double bond;

-   -    m is 0, 1, or 2;    -    p is 0 or 1; and wherein    -    when bond a is a single bond, then Z is —C(R³⁶)₂—, —C(═R³²)—,        —N(R³⁵)—, or —O—, wherein each R³⁶ is independently hydrogen or        R³¹; and    -    R³⁵ is hydrogen, C₁₋₆alkyl, —C(O)R, —S(O)₂R, —C(O)OR,        —C(O)N(R)₂, —S(O)₂OR, or —S(O)₂N(R)₂;    -    and when bond a is a double bond, then Z is —C(R³⁶)═ or —N═.    -   (9g) As group (9f), wherein when bond a is a single bond, then Z        is —C(R³⁶)₂— or —C(═R³²)—; and when bond a is a double bond,        then Z is —C(R³⁶)═ or —N═.    -   (9h) As group (91), wherein m is 0; when bond a is a single        bond, then Z is —C(R³⁶)₂— or —C(═R³²)—; and when bond a is a        double bond, then Z is —C(R³⁶)═ or —N═.    -   (91) As group (9f), wherein bond a is a single bond; and Z is        —C(R³⁶)₂— or —C(═R³²)—.    -   (9j) As group (9f), wherein bond a is a single bond; and Z is        —C(R³⁶)₂—.    -   (9k) As group (9f), wherein bond a is a single bond; and Z is        —C(═R³²)—.    -   (9l) As group (9f), wherein m is 0; bond a is a single bond; and        Z is —C(R³⁶)₂— or —C(═R³²)—.    -   (9m) As group (9f), wherein m is 0; bond a is a single bond; and        Z is —C(R³⁶)₂—.    -   (9n) As group (9f), wherein m is 0; bond a is a single bond; and        Z is —C(═R³²)—.    -   (9o) As group (9f), wherein bond a is a single bond; and Z is        —C(R³⁶)₂— or —C(═R³²)—, wherein each R³⁶ is independently        hydrogen, halogen, C₁₋₆alkyl, —C₁₋₆alkyl-OH, C₁₋₆haloalkyl, or        —OH, wherein        -   R³² is ═O, ═C(R³⁴)₂, =(spiro-C₃₋₈cycloalkyl), or            =(spiro-(3-8 membered heterocyclyl)), wherein each R³⁴ is            independently hydrogen, halogen, C₁₋₆alkyl, C₁₋₆haloalkyl,            C₃₋₈cycloalkyl, or 3-8 membered heterocyclyl.    -   (9p) As group (9f), wherein m is 0; bond a is a single bond; and        Z is —C(R³⁶)₂— or —C(═R³²)—, wherein each R³⁶ is independently        hydrogen, halogen, C₁₋₆alkyl, —C₁₋₆alkyl-OH, C₁₋₆haloalkyl, or        —OH, wherein        -   R³² is ═O, ═C(R³⁴)₂, =(spiro-C₃₋₈cycloalkyl), or            =(spiro-(3-8 membered heterocyclyl)), wherein each R³⁴ is            independently hydrogen, halogen, C₁₋₆alkyl, C₁₋₆haloalkyl,            C₃₋₈cycloalkyl, or 3-8 membered heterocyclyl.    -   (9q) As group (9f), wherein bond a is a single bond; and Z is        —N(R³⁵)— or —O—.    -   (9r) R³ is hydrogen, C₁₋₆alkyl, aryl, heteroaryl,        C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, 3-10 membered heterocyclyl, or        C₃₋₈cycloalkylC₁₋₆alkyl, wherein        -   the C₁₋₆alkyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, 3-10            membered heterocyclyl, and C₃₋₈cycloalkylC₁₋₆alkyl, are each            optionally substituted by one ═R³² group and one or two R³¹            groups;        -   the aryl and heteroaryl groups, are each optionally            substituted by one or two R³¹ groups; wherein        -   each R³¹ is independently halogen, cyano, nitro, C₁₋₆alkyl,            —C₁₋₆alkyl-R³³, C₁₋₆haloalkyl, —OR, —N(R)₂, —SR, —C(O)OR,            —C(O)N(R)₂, —C(O)R, —S(O)R, —S(O)OR, —S(O)N(R)₂, —S(O)₂R,            —S(O)₂OR, —S(O)₂N(R)₂, —OC(O)R, —OC(O)OR, —OC(O)N(R)₂,            —N(R)C(O)R, —N(R)C(O)OR, —N(R)C(O)N(R)₂, wherein R³³ is —OR,            —N(R)₂, or —SR; and        -   R³² is oxo, ═C(R³⁴)₂, =(spiro-C₃₋₈cycloalkyl), or            =(spiro-(3-10 membered heterocyclyl)), wherein each R³⁴ is            independently hydrogen, halogen, C₁₋₆alkyl, or            C₃₋₈cycloalkyl.    -   (9s) R³ is aryl, heteroaryl, C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl,        or 3-10 membered heterocyclyl, wherein the C₃₋₈cycloalkyl,        C₃₋₈cycloalkenyl, and 3-10 membered heterocyclyl are each        optionally substituted by one ═R³² group and one, two, three, or        four R³¹ groups; and        -   the aryl and heteroaryl are each optionally substituted by            one, two, three, or four R³¹ groups.        -   (9t) R³ is phenyl, cyclopentyl, cyclohexyl, cyclohexenyl,            furanyl, tetrahydropyranyl, piperidinyl, imidazolyl,            thiazolyl, each optionally substituted by one, two, three,            or four R³¹ groups, and wherein the cyclopentyl, cyclohexyl,            cyclohexenyl, andy piperidinyl groups are each optionally            substituted by one ═R³² group.    -   (9u) R³ is phenyl, cyclopentyl, cyclohexyl, cyclohex-1-en-1-yl,        cyclohex-3-en-1-yl, furan-2-yl, furan-3-yl,        tetrahydropyran-3-yl, tetrahydropyran-4-yl, piperidin-3-yl,        piperidin-4-yl, imidazol-2-yl, imidazol-4-yl, thiazol-2-yl,        thiazol-4-yl, thiazol-5-yl, each optionally substituted by one        or two R³¹ groups, and wherein the cyclopentyl, cyclohexyl,        cyclohexenyl, andy piperidinyl groups are each optionally        substituted by one ═R³² group.    -   (9v) Any one of groups (9a)-(9u), wherein each R is        independently hydrogen, C₁₋₆alkyl, C₁₋₆haloalkyl, aryl,        heteroaryl, C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, 3-10 membered        heterocyclyl, arylC₁₋₆alkyl, heteroarylC₁₋₆alkyl-,        C₃₋₈cycloalkylC₁₋₆alkyl-, C₃₋₈cycloalkenylC₁₋₆alkyl-, or (3-10        membered heterocyclyl)C₁₋₆-alkyl-.    -   (9w) Any one of groups (9a)-(9u), wherein each R is        independently hydrogen, C₁₋₆alkyl, C₁₋₆haloalkyl, phenyl, 5- or        6-membered heteroaryl, C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, 3-8        membered heterocyclyl, benzyl, (5- or 6-membered        heteroaryl)C₁₋₆alkyl-, C₃₋₈ cycloalkylC₁₋₆alkyl-,        C₃₋₈cycloalkenylC₁₋₆alkyl-, or (3-8 membered heterocyclyl)        C₁₋₆alkyl-.    -   (9x) Any one of groups (9a)-(9u), wherein each R is        independently hydrogen or C₁₋₆alkyl.

Particular embodiments of this aspect of the invention include compoundsof any one of the formulae (II), (II′), and (IIa)-(IId), each as definedin each of the following rows, wherein each entry is a group number asdefined above and a dash “-” indicates that the variable is as definedfor formula (II), or (II′), or defined according to any one of theapplicable variable definitions (7a)-(9t) [e.g., when R^(C) is a dash,it can be either as defined for Formula (II), or (II′), or any one ofdefinitions (8a)-(8g)]:

(II) n & R¹ R^(C) R³ (2)-1 IIb 7a 9b 8c (2)-2 IIc 7a 9b 8c (2)-3 IId 7a9b 8c (2)-4 IIf 7a 9b 8d (2)-5 IIg 7a 9b 8d (2)-6 IIh 7a 9b 8d (2)-7 IIb7a 9b 8g (2)-8 IIc 7a 9b 8g (2)-9 IId 7a 9b 8g (2)-10 IIf 7a 9e 8c(2)-11 IIg 7a 9e 8c (2)-12 IIh 7a 9e 8c (2)-13 IIb 7a 9e 8d (2)-14 IIc7a 9e 8d (2)-15 IId 7a 9e 8d (2)-16 IIf 7a 9e 8g (2)-17 IIg 7a 9e 8g(2)-18 IIh 7a 9e 8g (2)-19 IIb 7a 9v 8c (2)-20 IIc 7a 9v 8c (2)-21 IId7a 9v 8c (2)-22 IIf 7a 9v 8d (2)-23 IIg 7a 9v 8d (2)-24 IIh 7a 9v 8d(2)-25 IIb 7a 9v 8g (2)-26 IIc 7a 9v 8g (2)-27 IId 7a 9v 8g (2)-28 IIf7g 9b 8c (2)-29 IIg 7g 9b 8c (2)-30 IIh 7g 9b 8c (2)-31 IIb 7g 9b 8d(2)-32 IIc 7g 9b 8d (2)-33 IId 7g 9b 8d (2)-34 IIf 7g 9b 8g (2)-35 IIg7g 9b 8g (2)-36 IIh 7g 9b 8g (2)-37 IIb 7g 9e 8c (2)-38 IIc 7g 9e 8c(2)-39 IId 7g 9e 8c (2)-40 IIf 7g 9e 8d (2)-41 IIg 7g 9e 8d (2)-42 IIh7g 9e 8d (2)-43 IIb 7g 9e 8g (2)-44 IIc 7g 9e 8g (2)-45 IId 7g 9e 8g(2)-46 IIf 7g 9v 8c (2)-47 IIg 7g 9v 8c (2)-48 IIh 7g 9v 8c (2)-49 IIb7g 9v 8d (2)-50 IIc 7g 9v 8d (2)-51 IId 7g 9v 8d (2)-52 IIf 7g 9v 8g(2)-53 IIg 7g 9v 8g (2)-54 IIh 7g 9v 8g (2)-55 IIb 7h 9b 8c (2)-56 IIc7h 9b 8c (2)-57 IId 7h 9b 8c (2)-58 IIf 7h 9b 8d (2)-59 IIg 7h 9b 8d(2)-60 IIh 7h 9b 8d (2)-61 IIb 7h 9b 8g (2)-62 IIc 7h 9b 8g (2)-63 IId7h 9b 8g (2)-64 IIf 7h 9e 8c (2)-65 IIg 7h 9e 8c (2)-66 IIh 7h 9e 8c(2)-67 IIb 7h 9e 8d (2)-68 IIc 7h 9e 8d (2)-69 IId 7h 9e 8d (2)-70 IIf7h 9e 8g (2)-71 IIg 7h 9e 8g (2)-72 IIh 7h 9e 8g (2)-73 IIb 7h 9v 8c(2)-74 IIc 7h 9v 8c (2)-75 IId 7h 9v 8c (2)-76 IIf 7h 9v 8d (2)-77 IIg7h 9v 8d (2)-78 IIh 7h 9v 8d (2)-79 IIb 7h 9v 8g (2)-80 IIc 7h 9v 8g(2)-81 IId 7h 9v 8g (2)-82 IIf 7i 9b 8c (2)-83 IIg 7i 9b 8c (2)-84 IIh7i 9b 8c (2)-85 IIb 7i 9b 8d (2)-86 IIc 7i 9b 8d (2)-87 IId 7i 9b 8d(2)-88 IIf 7i 9b 8g (2)-89 IIg 7i 9b 8g (2)-90 IIh 7i 9b 8g (2)-91 IIb7i 9e 8c (2)-92 IIc 7i 9e 8c (2)-93 IId 7i 9e 8c (2)-94 IIf 7i 9e 8d(2)-95 IIg 7i 9e 8d (2)-96 IIh 7i 9e 8d (2)-97 IIb 7i 9e 8g (2)-98 IIc7i 9e 8g (2)-99 IId 7i 9e 8g (2)-100 IIf 7i 9v 8c (2)-101 IIg 7i 9v 8c(2)-102 IIh 7i 9v 8c (2)-103 IIb 7i 9v 8d (2)-104 IIc 7i 9v 8d (2)-105IId 7i 9v 8d (2)-106 IIf 7i 9v 8g (2)-107 IIg 7i 9v 8g (2)-108 IIh 7i 9v8g (2)-109 — — 9b 8c (2)-110 — — 9e 8c (2)-111 — — 9v 8c (2)-112 — — 9b8d (2)-113 — — 9e 8d (2)-114 — — 9v 8d (2)-115 — — 9b 8g (2)-116 — — 9e8g (2)-117 — — 9v 8g (2)-118 — 7a 9b 8c (2)-119 — 7a 9e 8c (2)-120 — 7a9v 8c (2)-121 — 7a 9b 8d (2)-122 — 7a 9e 8d (2)-123 — 7a 9v 8d (2)-124 —7a 9b 8g (2)-125 — 7a 9e 8g (2)-126 — 7a 9v 8g (2)-127 — 7g 9b 8c(2)-128 — 7g 9e 8c (2)-129 — 7g 9v 8c (2)-130 — 7g 9b 8d (2)-131 — 7g 9e8d (2)-132 — 7g 9v 8d (2)-133 — 7g 9b 8g (2)-134 — 7g 9e 8g (2)-135 — 7g9v 8g (2)-136 — 7h 9b 8c (2)-137 — 7h 9e 8c (2)-138 — 7h 9v 8c (2)-139 —7h 9b 8d (2)-140 — 7h 9e 8d (2)-141 — 7h 9v 8d (2)-142 — 7h 9b 8g(2)-143 — 7h 9e 8g (2)-144 — 7h 9v 8g (2)-145 — 7i 9b 8c (2)-146 — 7i 9e8c (2)-147 — 7i 9v 8c (2)-148 — 7i 9b 8d (2)-149 — 7i 9e 8d (2)-150 — 7i9v 8d (2)-151 — 7i 9b 8g (2)-152 — 7i 9e 8g (2)-153 — 7i 9v 8g (2)-154 —7a — 8c (2)-155 — 7a — 8d (2)-156 — 7a — 8g (2)-157 — 7g — 8c (2)-158 —7g — 8d (2)-159 — 7g — 8g (2)-160 — 7h — 8c (2)-161 — 7h — 8d (2)-162 —7h — 8g (2)-163 — 7i — 8c (2)-164 — 7i — 8d (2)-165 — 7i — 8g (2)-166 —7a 9b — (2)-167 — 7a 9e — (2)-168 — 7a 9b — (2)-169 — 7g 9e — (2)-170 —7g 9v — (2)-171 — 7g 9b — (2)-172 — 7h 9e — (2)-173 — 7h 9v — (2)-174 —7h 9b — (2)-175 — 7i 9e — (2)-176 — 7i 9v — (2)-177 — 7i 9b —

In another aspect, the present disclosure provides compounds that are

No. Structure Name 1254

2-(5H-imidazo[5,1-a]isoindol-5-yl)ethanol 1256

ethyl 2-(5H-imidazo[5,1-a]isoindol-5-yl)acetate 1258

2-(5H-imidazo[5,1-a]isoindol-5-yl)acetic acid 1259

2-(5H-imidazo[5,1-a]isoindol-5-yl)-N- methylacetamide 1273

(E)-5-(2-bromostyryl)-5H-imidazo[5,1- a]isoindole 1286

2-(6-chloro-5H-imidazo[5,1-a]isoindol-5-yl)-1- cyclohexylethanol 1287

2-(6-chloro-5H-imidazo[5,1-a]isoindol-5-yl)-1- cyclohexylethanone 1288

2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl 2- (((1R,2R,5S)-2-isopropyl-5-methylcyclohexyl)oxy)acetate 1299

2-(6-chloro-5H-imidazo[5,1-a]isoindol-5-yl)-1- cyclohexylethanol 1300

tert-butyl (4-(2-(5H-imidazo[5,1-a]isoindol-5-yl)acetyl)phenyl)carbamate 1301

1-(4-aminophenyl)-2-(5H-imidazo[5,1- a]isoindol-5-yl)ethanone 1302

tert-butyl (4-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)phenyl)carbamate 1303

1-(4-aminophenyl)-2-(5H-imidazo[5,1- a]isoindol-5-yl)ethanol 1304

1-cyclohexyl-2-(5H-imidazo[5,1-a]isoindol-5- yl)ethanol 1306

2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(3- nitrophenyl)ethanone 1307

2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(3- nitrophenyl)ethanol 1326

2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(2- nitrophenyl)ethanone 1327

2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(2- nitrophenyl)ethanol 1328

tert-butyl (2-(2-(5H-imidazo[5,1-a]isoindol-5-yl)acetyl)phenyl)carbamate 1329

tert-butyl (2-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)phenyl)carbamate 1330

1-(2-aminophenyl)-2-(5H-imidazo[5,1- a]isoindol-5-yl)ethanone 1331

1-(2-aminophenyl)-2-(5H-imidazo[5,1- a]isoindol-5-yl)ethanol 1334

1-(2-chlorophenyl)-2-(5H-imidazo[5,1- a]isoindol-5-yl)ethanone 1335

1-(5H-imidazo[5,1-a]isoindol-5-yl)-2- methylpropan-2-ol 1336

1-(2-chlorophenyl)-2-(5H-imidazo[5,1- a]isoindol-5-yl)ethanol 1343

1-(3-chlorophenyl)-2-(5H-imidazo[5,1- a]isoindol-5-yl)ethanol 1348

2-(5H-imidazo[5,1-a]isoindol-5-yl)-1- phenylethanone 1349

2-(5H-imidazo[5,1-a]isoindol-5-yl)-1- phenylethanol 1352

1-(2,4-dimethylfuran-3-yl)-2-(6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)ethanol; 1353

1-(3-chlorophenyl)-2-(5H-imidazo[5,1- a]isoindol-5-yl)ethanone 1356

1-cyclohexyl-2-(6-fluoro-5H-imidazo[5,1- a]isoindol-5-yl)ethanone 1357

1-cyclohexyl-2-(6-fluoro-5H-imidazo[5,1- a]isoindol-5-yl)ethanol 1358

2-(5H-imidazo[5,1-a]isoindol-5-yl)-1- (tetrahydro-2H-pyran-4-yl)ethanol1359

2-(7-chloro-5H-imidazo[5,1-a]isoindol-5-yl)-1- cyclohexylethanol 1360

(Z)-1-cyclohexyl-2-(5H-imidazo[5,1-a]isoindol- 5-yl)ethanone oxime 1362

1-cyclopentyl-2-(5H-imidazo[5,1-a]isoindol-5- yl)ethanol 1363

tert-butyl 4-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)piperidine-1-carboxylate 1364

1-cyclohexyl-2-(5H-imidazo[5,1-a]isoindol-5- yl)ethanamine 1367

tert-butyl (3-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)phenyl)carbamate 1369

1-(3-aminophenyl)-2-(5H-imidazo[5,1- a]isoindol-5-yl)ethanol 1370

2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(piperidin- 4-yl)ethanol 1371

4-(2-(6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-1-hydroxyethyl)cyclohexanol; 1372

1-cyclohexyl-2-(9-methoxy-5H-imidazo[5,1- a]isoindol-5-yl)ethanol 1373

5-(2-cyclohexyl-2-hydroxyethyl)-5H- imidazo[5,1-a]isoindol-9-ol 1374

2-(8-chloro-5H-imidazo[5,1-a]isoindol-5-yl)-1- cyclohexylethanol; 1375

1-(cyclohex-1-en-1-yl)-2-(5H-imidazo[5,1- a]isoindol-5-yl)ethanol; 1376

1-cyclohexyl-2-(8-fluoro-5H-imidazo[5,1- a]isoindol-5-yl)ethanol; 1378

2-(6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-1-(1,4-dioxaspiro[4.5]decan-8-yl)ethanol; 1379

4-(2-(6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-1-hydroxyethyl)cyclohexanone; 1381

2-(6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-1-(4-methylenecyclohexyl)ethanol; 1382

1-(cyclohex-3-en-1-yl)-2-(5H-imidazo[5,1- a]isoindol-5-yl)ethanol; 1383

1-(4-(hydroxymethyl)cyclohexyl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethanol; 1384

(4-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)piperidin-1-yl)(thiophen-2- yl)methanone; 1385

1-(4-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)piperidin-1-yl)ethanone; 1386

2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(4- methylenecyclohexyl)ethanol;1387

2-(6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-1-(4-methylcyclohexyl)ethanol; 1389

2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(1-methyl-1H-imidazol-4-yl)ethanol; 1390

2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(thiazol-4- yl)ethanol; 1391

2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(thiazol-5- yl)ethanol; 1392

1-(4-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)piperidin-1-yl)-2,2-dimethylpropan-1- one; 1393

2-(6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-1- (furan-2-yl)ethanol; 1394

2-(6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-1-(1-methyl-1H-imidazol-2-yl)ethanol; 1396

(1S)-1-cyclohexyl-2-(5H-imidazo[5,1-a]isoindol- 5-yl)ethanol; 1397

(1R)-1-cyclohexyl-2-(5H-imidazo[5,1- a]isoindol-5-yl)ethanol; 1398

2-(6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-1-(4-(iodomethylene)cyclohexyl)ethanol; 1400

1-cyclohexyl-2-(5H-imidazo[5,1-a]isoindol-5- yl)propan-1-ol; 1402

2-(5H-imidazo[5,1-a]isoindol-5-yl)acetonitrile; 1403

1-cyclohexyl-3-(6-fluoro-5H-imidazo[5,1- a]isoindol-5-yl)propan-2-ol;1404

1-cyclohexyl-3-(5H-imidazo[5,1-a]isoindol-5- yl)propan-2-ol; 1405

1-(4-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)piperidin-1-yl)-2-phenylethanone; 1406

1-(4,4-difluorocyclohexyl)-2-(6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)ethanol; 1407

1-(4,4-difluorocyclohexyl)-2-(5H-imidazo[5,1- a]isoindol-5-yl)ethanol;1409

2-(6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-1-(1-methyl-1H-imidazol-5-yl)ethanol; 1410

1-(4-(cyclopropylmethylene)cyclohexyl)-2-(6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)ethanol; 1411

2-(6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-1-(4-(propan-2-ylidene)cyclohexyl)ethanol; 1412

(E)-5-(2-cyclohexylvinyl)-5H-imidazo[5,1- a]isoindole; 1413

2-(9-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-1-(4-methylcyclohexyl)ethanol; 1414

1-(cyclohex-3-en-1-yl)-2-(6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)ethanol; 1415

(R)-1-cyclohexyl-2-((R)-5H-imidazo[5,1- a]isoindol-5-yl)ethanol 1416

(S)-1-cyclohexyl-2-((R)-5H-imidazo[5,1- a]isoindol-5-yl)ethanol 1417

(S)-1-cyclohexyl-2-((S)-5H-imidazo[5,1- a]isoindol-5-yl)ethanol 1418

(R)-1-cyclohexyl-2-((S)-5H-imidazo[5,1- a]isoindol-5-yl)ethanol 1419

1-cyclohexyl-2-(5H-imidazo[5,1-a]isoindol-5- ylidene)ethanol 1420

1-cyclohexyl-2-(5H-imidazo[5,1-a]isoindol-5- yl)ethyl acetate 1421

1-(4-(2-(benzyloxy)ethylidene)cyclohexyl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethanol 1422

1-(1-(benzylsulfonyl)piperidin-4-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethanol 1423

1-(4-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)piperidin-1-yl)-2-(pyrimidin-5- yl)ethanone 1424

2-(3,4-difluorophenyl)-1-(4-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)piperidin-1- yl)ethanone 1425

cyclohexyl(4-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)piperidin-1-yl)methanone 1426

methyl 4-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)cyclohexanecarboxylate 1427

1-cyclohexyl-2-(5H-imidazo[5,1-a]isoindol-5- yl)ethyl phenylcarbamate1428

4-(1-cyclohexyl-2-(5H-imidazo[5,1-a]isoindol-5- yl)ethoxy)-4-oxobutanoicacid 1429

4-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5- yl)ethyl)cyclohexanol 1430

1-(4-(hydroxymethyl)cyclohexyl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethanol 1431

1-cyclohexyl-2-(5H-imidazo[5,1-a]isoindol-5- yl)ethyl benzoate 1432

4-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)-N-(2-(methylsulfonamido)ethyl) cyclohexanecarboxamide 1433

(2S)-1-(1-cyclohexyl-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethoxy)-3-methyl-1-oxobutan-2- aminium chloride 1434

sodium 1-cyclohexyl-2-(5H-imidazo[5,1- a]isoindol-5-yl)ethyl phosphate1436

4-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)cyclohexanecarboxylic acid 1437

1-(4-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)piperidin-1-yl)-2-(pyridin-4- yl)ethanone 1438

2-(5H-imidazo[5,1-a]isoindol-5-yl)-1- (spiro[2.5]octan-6-yl)ethanol 1439

2-(4-fluorophenyl)-1-(4-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)piperidin-1- yl)ethanone 1440

(2S)-1-cyclohexyl-2-(5H-imidazo[5,1-a]isoindol- 5-yl)ethyl2-aminopropanoate 1441

1-(4-(2-hydroxyethylidene)cyclohexyl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethanol 1442

(2S)-1-cyclohexyl-2-(5H-imidazo[5,1-a]isoindol- 5-yl)ethylpyrrolidine-2-carboxylate 1443

(2S)-5-(1-cyclohexyl-2-(5H-imidazo[5,1- a]isoindol-5-yl)ethyl) 1-methyl2- aminopentanedioate 1447

1-(4-((S)-1-hydroxy-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)ethyl)piperidin-1-yl)-2- phenylethanone 1448

(3-fluoro-2-hydroxyphenyl)(4-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)piperidin- 1-yl)methanone 1449

4-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)-N-phenylpiperidine-1-carboxamide 1450

(4-fluorophenyl)(4-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)piperidin-1- yl)methanone 1451

(2S)-2-amino-1-(4-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)piperidin-1- yl)-3-phenylpropan-1-one1454

(4-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)piperidin-1-yl)((S)-pyrrolidin-2- yl)methanone 1455

(1R,4s)-4-(2-((S)-6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-1-hydroxyethyl)cyclohexyl benzoate 1456

(1R,4s)-4-(2-((S)-6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-1-hydroxyethyl)cyclohexanol 1458

1-(3-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)azetidin-1-yl)-2-phenylethanone 1459

3-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)-N-phenylazetidine-1-carboxamide 1460

tert-butyl 3-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)azetidine-1-carboxylate 1461

1-(azetidin-3-yl)-2-(5H-imidazo[5,1-a]isoindol- 5-yl)ethanol 1469

tert-butyl 4-((S)-1-hydroxy-2-((R)-5H-imidazo[5,1-a]isoindol-5-yl)ethyl)piperidine-1- carboxylate 1470

tert-butyl 4-((R)-1-hydroxy-2-((R)-5H-imidazo[5,1-a]isoindol-5-yl)ethyl)piperidine-1- carboxylate 1471

tert-butyl 4-((R)-1-hydroxy-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)ethyl)piperidine-1- carboxylate 1472

tert-butyl 4-((S)-1-hydroxy-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)ethyl)piperidine-1- carboxylate 1473

1-((1s,4s)-4-(benzyloxy)cyclohexyl)-2-(6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)ethanol 1474

2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(pyridin-3- yl)ethanol 1475

(1r,4r)-4-(2-(6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-1-hydroxyethyl)cyclohexanol 1476

4-((S)-1-hydroxy-2-((R)-5H-imidazo[5,1-a]isoindol-5-yl)ethyl)-N-phenylpiperidine-1- carboxamide 1477

4-((R)-1-hydroxy-2-((R)-5H-imidazo[5,1-a]isoindol-5-yl)ethyl)-N-phenylpiperidine-1- carboxamide 1478

4-((R)-1-hydroxy-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)ethyl)-N-phenylpiperidine-1- carboxamide 1479

4-((S)-1-hydroxy-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)ethyl)-N-phenylpiperidine-1- carboxamide 1480

1-(4-((R)-1-hydroxy-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)ethyl)piperidin-1-yl)-2- phenylethanone 1481

1-(4-((S)-1-hydroxy-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)ethyl)piperidin-1-yl)-2- phenylethanone 1482

(1R,4s)-4-((S)-2-((R)-6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-1-hydroxyethyl)cyclohexanol 1483

(1S,4s)-4-((R)-2-((R)-6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-1-hydroxyethyl)cyclohexanol 1484

(1S,4s)-4-((R)-2-((S)-6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-1-hydroxyethyl)cyclohexanol 1485

(1R,4s)-4-((S)-2-((S)-6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-1-hydroxyethyl)cyclohexanol 1486

(1S,4r)-4-((S)-2-((S)-6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-1-hydroxyethyl)cyclohexanol 1487

(1S,4r)-4-((S)-2-((R)-6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-1-hydroxyethyl)cyclohexanol 1488

(1R,4r)-4-((R)-2-((S)-6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-1-hydroxyethyl)cyclohexanol 1489

(1R,4r)-4-((R)-2-((R)-6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-1-hydroxyethyl)cyclohexanol 1490

1-(4-((S)-1-hydroxy-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)ethyl)piperidin-1-yl)-2-(tetrahydro-2H-pyran-4-yl)ethanone 1491

1-(4-((R)-1-hydroxy-2-((R)-5H-imidazo[5,1-a]isoindol-5-yl)ethyl)piperidin-1-yl)-2- phenylethanone 1492

N-((1s,4s)-4-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)cyclohexyl)benzamide 1493

1-(4-((S)-1-hydroxy-2-((R)-5H-imidazo[5,1-a]isoindol-5-yl)ethyl)piperidin-1-yl)-2- phenylethanone 1494

2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(1-(phenylcarbamoyl)piperidin-4-yl)ethyl phenylcarbamate 1495

4-((R)-1-hydroxy-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)ethyl)-N-((1r,4R)-4-hydroxycyclohexyl)piperidine-1-carboxamide 1496

4-((S)-1-hydroxy-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)ethyl)-N-(tetrahydro-2H-pyran-4-yl)piperidine-1-carboxamide 1497

4-((S)-1-hydroxy-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)ethyl)-N-((1r,4S)-4-hydroxycyclohexyl)piperidine-1-carboxamide 1498

1-((1r,4r)-(benzyloxy)cyclohexyl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethanol 1499

1-((1r,4r)-4-(benzyloxy)cyclohexyl)-2-(6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)ethanol 1500

1-(4-((R)-1-hydroxy-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)ethyl)piperidin-1-yl)-2-(tetrahydro-2H-pyran-4-yl)ethanone 1501

2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(pyridin-4- yl)ethanol 1502

2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(pyridin-2- yl)ethanol 1503

4-((R)-1-hydroxy-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)ethyl)-N-(tetrahydro-2H-pyran-4-yl)piperidine-1-carboxamide 1504

N-cyclohexyl-4-((R)-1-hydroxy-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)ethyl)piperidine-1- carboxamide 1505

N-((1r,4r)-4-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)cyclohexyl)benzamide 1506

1-((1r,4r)-4-(benzyloxy)cyclohexyl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethanol 1507

N-cyclopentyl-4-((R)-1-hydroxy-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)ethyl)piperidine-1- carboxamide 1508

2-(6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-1-(4-(trifluoromethyl)cyclohexyl)ethanol 1509

2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(4-(trifluoromethyl)cyclohexyl)ethanol 1511

2-(4-fluorophenyl)-1-(4-((R)-1-hydroxy-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)ethyl)piperidin- 1-yl)ethanone 1512

4-((R)-1-hydroxy-2-((S)-5H-imidazo[5,1- a]isoindol-5-yl)ethyl)-N-(4-(trifluoromethyl)phenyl)piperidine-1- carboxamide 1513

(4-((R)-1-hydroxy-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)ethyl)piperidin-1-yl)(1H- imidazol-1-yl)methanone

1-(5H-imidazo[5,1-a]isoindol-5-yl)-3- methylbutan-2-ol

2-(5H-imidazo[5,1-a]isoindol-5-yl)-1- (tetrahydro-2H-pyran-3-yl)ethanol

2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(piperidin- 3-yl)ethanol

1-cyclohexyl-2-((R)-5H-imidazo[5,1-a]isoindol- 5-yl)ethanol

1-cyclohexyl-2-((S)-5H-imidazo[5,1-a]isoindol- 5-yl)ethanol

(1S)-1-cyclohexyl-2-(5H-imidazo[5,1-a]isoindol- 5-yl)ethanol

(1R)-1-cyclohexyl-2-(5H-imidazo[5,1- a]isoindol-5-yl)ethanol

1-cyclohexyl-3-(5H-imidazo[5,1-a]isoindol-5- yl)propan-1-ol

1-cyclohexyl-2-(9-fluoro-5H-imidazo[5,1- a]isoindol-5-yl)ethanol

N-(4-(l-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)phenyl)-2-(tetrahydro-2H-pyran-4- yl)acetamide

2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(1H- imidazol-2-yl)ethanol

2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(1H- imidazol-4-yl)ethanol

2-(6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-1- (thiazol-2-yl)ethanol

(5S)-5-(2-cyclohexyl-2-hydroxyethyl)-5H- imidazo[5,1-a]isoindol-6-ol

1-(2-aminocyclohexyl)-2-(5H-imidazo[5,1- a]isoindol-5-yl)ethanol

N-(1-cyclohexyl-2-(5H-imidazo[5,1-a]isoindol- 5-yl)ethyl)acetamide

N-(2-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)cyclohexyl)acetamide

1-cyclohexyl-2-(5H-imidazo[5,1-a]isoindol-5- yl)-N-methylethanamine

2-((1-cyclohexyl-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)ethyl)amino)ethanesulfonamide

2-(6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-1-(1-methylpiperidin-4-yl)ethanol

1-(4-aminocyclohexyl)-2-(5H-imidazo[5,1- a]isoindol-5-yl)ethanol

N-(4-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)cyclohexyl)acetamide

1-(4-(aminomethyl)cyclohexyl)-2-(5H- imidazo[5,1-a]isoindol-5-yl)ethanol

4-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)cyclohexanecarboxamide

1-(3-aminocyclohexyl)-2-(5H-imidazo[5,1- a]isoindol-5-yl)ethanol

2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(piperidin- 3-yl)ethanol

2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-((1r,4r)-4-(pyridin-2-ylmethoxy)cyclohexyl)ethanol

2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-((1r,4r)-4-(pyridin-3-ylmethoxy)cyclohexyl)ethanol

2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-((1r,4r)-4-(pyridin-4-ylmethoxy)cyclohexyl)ethanol

2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-((1r,4r)-4-(pyridin-4-ylmethoxy)cyclohexyl)ethanol

1-((1r,4r)-4-((2-aminopyridin-4-yl)methoxy)cyclohexyl)-2-(5H-imidazo[5,1- a]isoindol-5-yl)ethanol

2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-((1r,4r)-4-(pyrazin-2-ylmethoxy)cyclohexyl)ethanol

2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-((1r,4r)-4-(pyrimidin-5-ylmethoxy)cyclohexyl)ethanol

1-((1r,4r)-4-((6-aminopyridin-2-yl)methoxy)cyclohexyl)-2-(5H-imidazo[5,1- a]isoindol-5-yl)ethanol

1-((1r,4r)-4-((6-aminopyridin-3-yl)methoxy)cyclohexyl)-2-(5H-imidazo[5,1- a]isoindol-5-yl)ethanol

1-((1r,4r)-4-((3-aminopyridin-2-yl)methoxy)cyclohexyl)-2-(5H-imidazo[5,1- a]isoindol-5-yl)ethanol

1-((1r,4r)-4-((2-aminopyrimidin-5-yl)methoxy)cyclohexyl)-2-(5H-imidazo[5,1- a]isoindol-5-yl)ethanol

1-((1r,4r)-4-((4-aminopyrimidin-5-yl)methoxy)cyclohexyl)-2-(5H-imidazo[5,1- a]isoindol-5-yl)ethanol

1-((1r,4r)-4-((5-aminopyridin-2-yl)methoxy)cyclohexyl)-2-(5H-imidazo[5,1- a]isoindol-5-yl)ethanol

4-((((1r,4r)-4-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)cyclohexyl)oxy)methyl)- N,N-dimethylbenzamide

3-((((1r,4r)-4-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)cyclohexyl)oxy)methyl)- N,N-dimethylbenzamide

2-((((1r,4r)-4-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)cyclohexyl)oxy)methyl)- N,N-dimethylbenzamide

4-((((1r,4r)-4-(1-hydroxy-2-(5H-imidazo[5,1- a]isoindol-5-yl)ethyl)cyclohexyl)oxy)methyl) benzenesulfonamide

3-((((1r,4r)-4-(1-hydroxy-2-(5H-imidazo[5,1- a]isoindol-5-yl)ethyl)cyclohexyl)oxy)methyl) benzenesulfonamide

2-((((1r,4r)-4-(1-hydroxy-2-(5H-imidazo[5,1- a]isoindol-5-yl)ethyl)cyclohexyl)oxy)methyl) benzenesulfonamide

4-((((1r,4r)-4-(1-hydroxy-2-(5H-imidazo[5,1- a]isoindol-5-yl)ethyl)cyclohexyl)oxy)methyl)benzamide

3-((((1r,4r)-4-(1-hydroxy-2-(5H-imidazo[5,1- a]isoindol-5-yl)ethyl)cyclohexyl)oxy)methyl)benzamide

2-((((1r,4r)-4-(1-hydroxy-2-(5H-imidazo[5,1- a]isoindol-5-yl)ethyl)cyclohexyl)oxy)methyl)benzamide

methyl 4-((((1r,4r)-4-(1-hydroxy-2-(5H- imidazo[5,1-a]isoindol-5-yl)ethyl)cyclohexyl)oxy)methyl)benzoate

methyl 3-((((1r,4r)-4-(1-hydroxy-2-(5H- imidazo[5,1-a]isoindol-5-yl)ethyl)cyclohexyl)oxy)methyl)benzoate

methyl 2-((((1r,4r)-4-(1-hydroxy-2-(5H- imidazo[5,1-a]isoindol-5-yl)ethyl)cyclohexyl)oxy)methyl)benzoate

2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-((1r,4r)-4-methoxycyclohexyl)ethanol

1-((1r,4r)-4-ethoxycyclohexyl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethanol

2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-((1r,4r)-4-isopropoxycyclohexyl)ethanol

1-((1r,4r)-4-(cyclopropylmethoxy)cyclohexyl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethanol

1-((1r,4r)-4-(cyclopentylmethoxy)cyclohexyl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethanol

2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-((1r,4r)-4-(thiophen-2-ylmethoxy)cyclohexyl)ethanol

1-((1r,4r)-4-((1H-indol-3-yl)oxy)cyclohexyl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethanol

1-((1r,4r)-4-((1H-indol-5-yl)oxy)cyclohexyl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethanol

2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(4- ((tetrahydro-2H-pyran-4-yl)methoxy)cyclohexyl)ethanol

4-(((4-(1-hydroxy-2-(5H-imidazo[5,1-a] isoindol-5-yl)ethyl)cyclohexyl)oxy)methyl) benzenesulfonamide

2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(4-(oxazol-2-ylmethoxy)cyclohexyl)ethanol

2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(4-(thiazol-2-ylmethoxy)cyclohexyl)ethanol

2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(1-(1-imino-2-phenylethyl)piperidin-4-yl)ethanol

4-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)-N-phenylpiperidine-1-carboximidamide

4-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)-N-(pyridin-4-yl)piperidine-1- carboximidamide

4-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)-N-(tetrahydro-2H-pyran-4- yl)piperidine-1-carboximidamide

N-(4-cyanophenyl)-4-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)piperidine-1- carboxamide

N-(tert-butyl)-4-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)piperidine-1-carboxamide

N-(tert-butyl)-4-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)piperidine-1-sulfonamide

1-(4-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)piperidin-1-yl)-2-(3- hydroxyphenyl)ethanone

2-(1-(azetidine-1-carbonyl)piperidin-4-yl)-2-hydroxy-1-(4-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)piperidin-1-yl)ethanone

2-cyclopentyl-1-(4-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)piperidin-1- yl)ethanone

1-(4-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)piperidin-1-yl)-2-(2-methylthiazol-5- yl)ethanone

1-(4-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)piperidin-1-yl)-2-(2-methylthiazol-5- yl)ethanone

N-cyclohexyl-N-hydroxy-4-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)piperidine-1- carboxamide

N-(4-(2-(4-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)piperidin-1-yl)-2-oxoethyl)phenyl)methanesulfonamide

N-cyclopropyl-N-hydroxy-4-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)piperidine-1- carboxamide

3,3-difluoro-1-(4-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)piperidin-1- yl)butan-1-one

1-(4-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)piperidin-1-yl)-2-(p-tolyl)ethanone

1-(1-(4-aminopyrimidin-2-yl)piperidin-4-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethanol

1-(1-(2-aminopyrimidin-4-yl)piperidin-4-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethanol

N-cyclopropyl-4-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)piperidine-1-carboxamide

2-cyclopropyl-1-(4-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)piperidin-1- yl)ethanone

2-(4-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)cyclohexylidene)acetonitrile

4-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)-N-(4-(trifluoromethyl)thiazol-2- yl)piperidine-1-carboxamide

4-(2-(4-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)piperidin-1-yl)-2- oxoethyl)benzamide

1-(4-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)piperidin-1-yl)-2-(4- (methylsulfonyl)phenyl)ethanone

4-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5- yl)ethyl)-N-((1r,4r)-4-methylcyclohexyl)piperidine-1-carboxamide

1-(4-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)piperidin-1-yl)-3,3-dimethylbutan-1- one

4-(2-(4-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)piperidin-1-yl)-2- oxoethyl)benzenesulfonamide

N-(tert-butyl)-4-(2-(4-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)piperidin-1-yl)-2-oxoethyl)benzenesulfonamide

4-(2-(4-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)piperidin-1-yl)-2- oxoethyl)benzoic acid

1-(4-(difluoromethylene)cyclohexyl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethanol

2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(4-(2,2,2-trifluoroethylidene)cyclohexyl)ethanol

N-benzyl-4-(2-(6-fluoro-5H-imidazo[5,1- a]isoindol-5-yl)-1-hydroxyethyl)cyclohexanecarboxamide

4-(2-(6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)- 1-hydroxyethyl)-N-phenylcyclohexanecarboxamide

N-(4-(2-(6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-1-hydroxyethyl)cyclohexyl)benzamide

1-(4-(2-(6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-1-hydroxyethyl)cyclohexyl)-3-phenylurea

N-(4-(2-(6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-1-hydroxyethyl)cyclohexyl)-2- phenylacetamide and pharmaceuticallyacceptable salts thereof.

In another aspect, the present disclosure provides compounds andpharmaceutical compositions comprising the compounds according to anyone of the preceding aspects of the invention or any embodiment thereof,together with a pharmaceutically acceptable excipient, diluent, orcarrier.

In another aspect, the invention provides methods for treatingindoleamine 2,3-dioxygenase (IDO) mediated immunosuppression in asubject in need thereof, comprising administering an effectiveindoleamine 2,3-dioxygenase inhibiting amount of a compound or apharmaceutical composition according to any of the preceding aspects ofthe invention or any embodiment thereof.

In one embodiment, the immunosuppression is associated with aninfectious disease, or cancer.

In another embodiment, the immunosuppression is associated with aninfectious disease and the infectious disease is a viral infectionselected from the group consisting of: hepatitis C virus (HCV), humanpapilloma virus (HPV), cytomegalovirus (CMV), Epstein-Barr virus (EBV),poliovirus, varicella zoster virus, coxsackie virus, humanimmunodeficiency virus (HIV).

In another embodiment, the immunosuppression is immunosupressionassociated with HIV-1 infection.

In another embodiment, the immunosuppression is associated with acancer.

In an embodiment, the immunosuppression is tumor-specificimmunosuppression associated with cancer.

In another embodiment, the immunosuppression is associated with acancer, wherein the cancer is colon, pancreas, breast, prostate, lung,brain, ovary, cervix, testes, renal, head, or neck cancer, or lymphoma,leukemia, or melanoma.

In another aspect, the invention provides the use of compounds describedby any one of the preceding aspects (and any embodiment thereof), asdefined above, for the preparation of a medicament for the treatment ofmedical conditions that benefit from the inhibition of enzymaticactivity of indoleamine-2,3-dioxygenase. Medical conditions contemplatedin this aspect include all the conditions described herein.

In another aspect, the invention provides a use of compounds describedby any one of the preceding aspects (and any embodiment thereof), asdefined above, for the preparation of a medicament to stimulate T cellproliferation or to reverse an immunologic state of anergy orimmunosuppression.

In one embodiment, the anergy or immunosuppression is caused byexpression of the enzyme indoleamine-2,3-dioxygenase.

In another aspect, the invention provides the use of compounds describedby any one of the preceding aspects (and any embodiment thereof), asdefined above, for the preparation of a medicament for the treatment ofimmunosuppression associated with cancer, infectious diseases, or viralinfections.

In one embodiment, the invention provides the use of compounds describedin to any one of the preceding aspects (and any embodiment thereof), asdefined above, for the preparation of a medicament for the treatment oftumor-specific immunosuppression associated with cancer. Preferably, thecancer is cancer of the colon, pancreas, breast, prostate, lung, brain,ovary, cervix, testes, renal, or head and neck, lymphoma, leukemia,melanoma, and the like.

In another embodiment, the invention provides the use of compoundsdescribed in any of the preceding aspects (and any embodiment thereof),as defined above, and embodiments thereof as defined above, for thepreparation of a medicament for the treatment of infectious diseaseswhere the infectious disease is a viral infection. Preferably, the viralinfection is selected from the group consisting of: influenza, hepatitisC virus (HCV), human papilloma virus (HPV), cytomegalovirus (CMV),Epstein-Barr virus (EBV), varicella zoster virus, poliovirus, coxsackievirus, and human immunodeficiency virus (HIV). More preferably, theviral infection is human immunodeficiency virus (HIV).

DEFINITIONS

Terms used herein may be preceded and/or followed by a single dash, “-”,or a double dash, “=”, to indicate the bond order of the bond betweenthe named substituent and its parent moiety; a single dash indicates asingle bond and a double dash indicates a double bond or a pair ofsingle bonds in the case of a spiro-substituent. In the absence of asingle or double dash it is understood that a single bond is formedbetween the substituent and its parent moiety; further, substituents areintended to be read “left to right” unless a dash indicates otherwise.For example, C₁-C₆alkoxycarbonyloxy and —OC(O)C₁-C₆alkyl indicate thesame functionality; similarly arylalkyl, arylalkyl-, and -alkylarylindicate the same functionality.

Further, certain terms herein may be used as both monovalent anddivalent linking radicals as would be familiar to those skilled in theart, and by their presentation linking between two other moieties. Forexample, an alkyl group can be both a monovalent radical or divalentradical; in the latter case, it would be apparent to one skilled in theart that an additional hydrogen atom is removed from a monovalent alkylradical to provide a suitable divalent moiety.

The term “alkenyl” as used herein, means a straight or branched chainhydrocarbon containing from 2 to 10 carbons, unless otherwise specified,and containing at least one carbon-carbon double bond. Representativeexamples of alkenyl include, but are not limited to, ethenyl,2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl,2-heptenyl, 2-methyl-1-heptenyl, 3-decenyl, and3,7-dimethylocta-2,6-dienyl.

The term “alkoxy” as used herein, means an alkyl group, as definedherein, appended to the parent molecular moiety through an oxygen atom.Representative examples of alkoxy include, but are not limited to,methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, andhexyloxy.

The term “alkyl” as used herein, means a straight or branched chainhydrocarbon containing from 1 to 10 carbon atoms, unless otherwisespecified. Representative examples of alkyl include, but are not limitedto, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl,tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl,2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, andn-decyl. When an “alkyl” group is a linking group between two othermoieties, then it may also be a straight or branched chain; examplesinclude, but are not limited to —CH₂—, —CH₂CH₂—, —CH₂CH₂CHC(CH₃)—,—CH₂CH(CH₂CH₃)CH₂—.

The term “aryl,” as used herein, means a phenyl (i.e., monocyclic aryl),or a bicyclic ring system containing at least one phenyl ring or anaromatic bicyclic ring containing only carbon atoms in the aromaticbicyclic ring system. The bicyclic aryl can be azulenyl, naphthyl, or aphenyl fused to a monocyclic cycloalkyl, a monocyclic cycloalkenyl, or amonocyclic heterocyclyl. The bicyclic aryl is attached to the parentmolecular moiety through any carbon atom contained within the phenylportion of the bicyclic system, or any carbon atom with the napthyl orazulenyl ring. The fused monocyclic cycloalkyl or monocyclicheterocyclyl portions of the bicyclic aryl are optionally substitutedwith one or two oxo and/or thia groups. Representative examples of thebicyclic aryls include, but are not limited to, azulenyl, naphthyl,dihydroinden-1-yl, dihydroinden-2-yl, dihydroinden-3-yl,dihydroinden-4-yl, 2,3-dihydroindol-4-yl, 2,3-dihydroindol-5-yl,2,3-dihydroindol-6-yl, 2,3-dihydroindol-7-yl, inden-1-yl, inden-2-yl,inden-3-yl, inden-4-yl, dihydronaphthalen-2-yl, dihydronaphthalen-3-yl,dihydronaphthalen-4-yl, dihydronaphthalen-1-yl,5,6,7,8-tetrahydronaphthalen-1-yl, 5,6,7,8-tetrahydronaphthalen-2-yl,2,3-dihydrobenzofuran-4-yl, 2,3-dihydrobenzofuran-5-yl,2,3-dihydrobenzofuran-6-yl, 2,3-dihydrobenzofuran-7-yl,benzo[d][1,3]dioxol-4-yl, benzo[d][1,3]dioxol-5-yl,2H-chromen-2-on-5-yl, 2H-chromen-2-on-6-yl, 2H-chromen-2-on-7-yl,2H-chromen-2-on-8-yl, isoindoline-1,3-dion-4-yl,isoindoline-1,3-dion-5-yl, inden-1-on-4-yl, inden-1-on-5-yl,inden-1-on-6-yl, inden-1-on-7-yl, 2,3-dihydrobenzo[b][1,4]dioxan-5-yl,2,3-dihydrobenzo[b][1,4]dioxan-6-yl,2H-benzo[b][1,4]oxazin3(4H)-on-5-yl,2H-benzo[b][1,4]oxazin3(4H)-on-6-yl,2H-benzo[b][1,4]oxazin3(4H)-on-7-yl,2H-benzo[b][1,4]oxazin3(4H)-on-8-yl, benzo[d]oxazin-2(3H)-on-5-yl,benzo[d]oxazin-2(3H)-on-6-yl, benzo[d]oxazin-2(3H)-on-7-yl,benzo[d]oxazin-2(3H)-on-8-yl, quinazolin-4(3H)-on-5-yl,quinazolin-4(3H)-on-6-yl, quinazolin-4(3H)-on-7-yl,quinazolin-4(3H)-on-8-yl, quinoxalin-2(1H)-on-5-yl,quinoxalin-2(1H)-on-6-yl, quinoxalin-2(1H)-on-7-yl,quinoxalin-2(1H)-on-8-yl, benzo[d]thiazol-2(3H)-on-4-yl,benzo[d]thiazol-2(3H)-on-5-yl, benzo[d]thiazol-2(3H)-on-6-yl, and,benzo[d]thiazol-2(3H)-on-7-yl. In certain embodiments, the bicyclic arylis (i) naphthyl or (ii) a phenyl ring fused to either a 5 or 6 memberedmonocyclic cycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, or a 5or 6 membered monocyclic heterocyclyl, wherein the fused cycloalkyl,cycloalkenyl, and heterocyclyl groups are optionally substituted withone or two groups which are independently oxo or thia.

The term “arylalkyl,” “-alkylaryl,” and “arylalkyl-” as used herein,means an aryl group, as defined herein, appended to the parent molecularmoiety through an alkyl group, as defined herein. Representativeexamples of arylalkyl include, but are not limited to, benzyl,2-phenylethyl, 3-phenylpropyl, and 2-naphth-2-ylethyl.

The terms “cyano” and “nitrile” as used herein, mean a —CN group.

The term “cycloalkyl” as used herein, means a monocyclic or a bicycliccycloalkyl ring system. Monocyclic ring systems are cyclic hydrocarbongroups containing from 3 to 8 carbon atoms, where such groups can besaturated or unsaturated, but not aromatic. In certain embodiments,cycloalkyl groups are fully saturated. Examples of monocycliccycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl,cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. Bicycliccycloalkyl ring systems are bridged monocyclic rings or fused bicyclicrings. Bridged monocyclic rings contain a monocyclic cycloalkyl ringwhere two non-adjacent carbon atoms of the monocyclic ring are linked byan alkylene bridge of between one and three additional carbon atoms(i.e., a bridging group of the form —(CH₂)_(w)—, where w is 1, 2, or 3).Representative examples of bicyclic ring systems include, but are notlimited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane,bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, andbicyclo[4.2.1]nonane. Fused bicyclic cycloalkyl ring systems contain amonocyclic cycloalkyl ring fused to either a phenyl, a monocycliccycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocyclyl, or amonocyclic heteroaryl. The bridged or fused bicyclic cycloalkyl isattached to the parent molecular moiety through any carbon atomcontained within the monocyclic cycloalkyl ring. Cycloalkyl groups areoptionally substituted with one or two groups which are independentlyoxo or thia. In certain embodiments, the fused bicyclic cycloalkyl is a5 or 6 membered monocyclic cycloalkyl ring fused to either a phenylring, a 5 or 6 membered monocyclic cycloalkyl, a 5 or 6 memberedmonocyclic cycloalkenyl, a 5 or 6 membered monocyclic heterocyclyl, or a5 or 6 membered monocyclic heteroaryl, wherein the fused bicycliccycloalkyl is optionally substituted by one or two groups which areindependently oxo or thia.

“Cycloalkenyl” as used herein refers to a monocyclic or a bicycliccycloalkenyl ring system. Monocyclic ring systems are cyclic hydrocarbongroups containing from 3 to 8 carbon atoms, where such groups areunsaturated (i.e., containing at least one annular carbon-carbon doublebond), but not aromatic. Examples of monocyclic ring systems includecyclopentenyl and cyclohexenyl. Bicyclic cycloalkenyl rings are bridgedmonocyclic rings or a fused bicyclic rings. Bridged monocyclic ringscontain a monocyclic cycloalkenyl ring where two non-adjacent carbonatoms of the monocyclic ring are linked by an alkylene bridge of betweenone and three additional carbon atoms (i.e., a bridging group of theform —(CH₂)_(w)—, where w is 1, 2, or 3). Representative examples ofbicyclic cycloalkenyls include, but are not limited to, norbornenyl andbicyclo[2.2.2]oct-2-enyl. Fused bicyclic cycloalkenyl ring systemscontain a monocyclic cycloalkenyl ring fused to either a phenyl, amonocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclicheterocyclyl, or a monocyclic heteroaryl. The bridged or fused bicycliccycloalkenyl is attached to the parent molecular moiety through anycarbon atom contained within the monocyclic cycloalkenyl ring.Cycloalkenyl groups are optionally substituted with one or two groupswhich are independently oxo or thia.

The term “halo” or “halogen” as used herein, means —Cl, —Br, —I or —F.

The term “haloalkyl” as used herein, means at least one halogen, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein. Representative examples of haloalkyl include,but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl,pentafluoroethyl, and 2-chloro-3-fluoropentyl.

The term “heteroaryl,” as used herein, means a monocyclic heteroaryl ora bicyclic ring system containing at least one heteroaromatic ring. Themonocyclic heteroaryl can be a 5 or 6 membered ring. The 5 membered ringconsists of two double bonds and one, two, three or four nitrogen atomsand optionally one oxygen or sulfur atom. The 6 membered ring consistsof three double bonds and one, two, three or four nitrogen atoms. The 5or 6 membered heteroaryl is connected to the parent molecular moietythrough any carbon atom or any nitrogen atom contained within theheteroaryl. Representative examples of monocyclic heteroaryl include,but are not limited to, furyl, imidazolyl, isoxazolyl, isothiazolyl,oxadiazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl,pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl,triazolyl, and triazinyl. The bicyclic heteroaryl consists of amonocyclic heteroaryl fused to a phenyl, a monocyclic cycloalkyl, amonocyclic cycloalkenyl, a monocyclic heterocyclyl, or a monocyclicheteroaryl. The fused cycloalkyl or heterocyclyl portion of the bicyclicheteroaryl group is optionally substituted with one or two groups whichare independently oxo or thia. When the bicyclic heteroaryl contains afused cycloalkyl, cycloalkenyl, or heterocyclyl ring, then the bicyclicheteroaryl group is connected to the parent molecular moiety through anycarbon or nitrogen atom contained within the monocyclic heteroarylportion of the bicyclic ring system. When the bicyclic heteroaryl is amonocyclic heteroaryl fused to a phenyl ring or a monocyclic heteroaryl,then the bicyclic heteroaryl group is connected to the parent molecularmoiety through any carbon atom or nitrogen atom within the bicyclic ringsystem. Representative examples of bicyclic heteroaryl include, but arenot limited to, benzimidazolyl, benzofuranyl, benzothienyl,benzoxadiazolyl, benzoxathiadiazolyl, benzothiazolyl, cinnolinyl,5,6-dihydroquinolin-2-yl, 5,6-dihydroisoquinolin-1-yl, furopyridinyl,indazolyl, indolyl, isoquinolinyl, naphthyridinyl, quinolinyl, purinyl,5,6,7,8-tetrahydroquinolin-2-yl, 5,6,7,8-tetrahydroquinolin-3-yl,5,6,7,8-tetrahydroquinolin-4-yl, 5,6,7,8-tetrahydroisoquinolin-1-yl,thienopyridinyl, 4,5,6,7-tetrahydrobenzo[c][1,2,5]oxadiazolyl, and6,7-dihydrobenzo[c][1,2,5]oxadiazol-4(5H)-onyl. In certain embodiments,the fused bicyclic heteroaryl is a 5 or 6 membered monocyclic heteroarylring fused to either a phenyl ring, a 5 or 6 membered monocycliccycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, a 5 or 6 memberedmonocyclic heterocyclyl, or a 5 or 6 membered monocyclic heteroaryl,wherein the fused cycloalkyl, cycloalkenyl, and heterocyclyl groups areoptionally substituted with one or two groups which are independentlyoxo or thia.

The term “heteroarylalkyl” and “-alkylheteroaryl” as used herein, meansa heteroaryl, as defined herein, appended to the parent molecular moietythrough an alkyl group, as defined herein. Representative examples ofheteroarylalkyl include, but are not limited to, fur-3-ylmethyl,1H-imidazol-2-ylmethyl, 1H-imidazol-4-ylmethyl, 1-(pyridin-4-yl)ethyl,pyridin-3-ylmethyl, pyridin-4-ylmethyl, pyrimidin-5-ylmethyl,2-(pyrimidin-2-yl)propyl, thien-2-ylmethyl, and thien-3-ylmethyl.

The term “heterocyclyl” as used herein, means a monocyclic heterocycleor a bicyclic heterocycle. The monocyclic heterocycle is a 3, 4, 5, 6 or7 membered ring containing at least one heteroatom independentlyselected from the group consisting of O, N, and S where the ring issaturated or unsaturated, but not aromatic. The 3 or 4 membered ringcontains 1 heteroatom selected from the group consisting of O, N and S.The 5 membered ring can contain zero or one double bond and one, two orthree heteroatoms selected from the group consisting of O, N and S. The6 or 7 membered ring contains zero, one or two double bonds and one, twoor three heteroatoms selected from the group consisting of O, N and S.The monocyclic heterocycle is connected to the parent molecular moietythrough any carbon atom or any nitrogen atom contained within themonocyclic heterocycle. Representative examples of monocyclicheterocycle include, but are not limited to, azetidinyl, azepanyl,aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl,1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl,isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl,oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, piperazinyl,piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl,pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl,thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl,1,1-dioxidothiomorpholinyl (thiomorpholine sulfone), thiopyranyl, andtrithianyl. The bicyclic heterocycle is a monocyclic heterocycle fusedto either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl,a monocyclic heterocycle, or a monocyclic heteroaryl. The bicyclicheterocycle is connected to the parent molecular moiety through anycarbon atom or any nitrogen atom contained within the monocyclicheterocycle portion of the bicyclic ring system. Representative examplesof bicyclic heterocyclyls include, but are not limited to,2,3-dihydrobenzofuran-2-yl, 2,3-dihydrobenzofuran-3-yl, indolin-1-yl,indolin-2-yl, indolin-3-yl, 2,3-dihydrobenzothien-2-yl,decahydroquinolinyl, decahydroisoquinolinyl, octahydro-1H-indolyl, andoctahydrobenzofuranyl. Heterocyclyl groups are optionally substitutedwith one or two groups which are independently oxo or thia. In certainembodiments, the bicyclic heterocyclyl is a 5 or 6 membered monocyclicheterocyclyl ring fused to phenyl ring, a 5 or 6 membered monocycliccycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, a 5 or 6 memberedmonocyclic heterocyclyl, or a 5 or 6 membered monocyclic heteroaryl,wherein the bicyclic heterocyclyl is optionally substituted by one ortwo groups which are independently oxo or thia.

The term “hydroxy” as used herein, means an —OH group.

The term “nitro” as used herein, means a —NO₂ group.

The term “oxo” as used herein means a ═O group.

The term “saturated” as used herein means the referenced chemicalstructure does not contain any multiple carbon-carbon bonds. Forexample, a saturated cycloalkyl group as defined herein includescyclohexyl, cyclopropyl, and the like.

The term “spiro” as used herein refers to a cyclic moiety formed by thesubstituted atom and two available substitutable postions on that sameatom. For example, moiety such as

where R is a spiro-cycloalkyll= group includes compounds such as

where the spiro-cyclopentyl group is the R group attached to the parentcyclohexyl ring by two single bonds. Similarly, where R is aspiro-heterocyclyl group, such compounds include

where the spiro-1,3-dioxolanyl ring is the R group attached to theparent cyclohexyl ring by two single bonds.

The term “thia” as used herein means a ═S group.

The term “unsaturated” as used herein means the referenced chemicalstructure contains at least one multiple carbon-carbon bond, but is notaromatic. For example, a unsaturated cycloalkyl group as defined hereinincludes cyclohexenyl, cyclopentenyl, cyclohexadienyl, and the like.

As used herein, the term “cell” is meant to refer to a cell that is invitro, ex vivo or in vivo. In some embodiments, an ex vivo cell can bepart of a tissue sample excised from an organism such as a mammal. Insome embodiments, an in vitro cell can be a cell in a cell culture. Insome embodiments, an in vivo cell is a cell living in an organism suchas a mammal.

As used herein, the term “contacting” refers to the bringing together ofindicated moieties in an in vitro system or an in vivo system. Forexample, “contacting” the IDO enzyme with a compound includes theadministration of a compound described herein to an individual orpatient, such as a human, having IDO, as well as, for example,introducing a compound into a sample containing a cellular or purifiedpreparation containing the IDO enzyme.

As used herein, the term “individual” or “patient,” usedinterchangeably, refers to any animal, including mammals, preferablymice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep,horses, or primates, and most preferably humans.

As used herein, the phrase “therapeutically effective amount” refers tothe amount of active compound or pharmaceutical agent that elicits thebiological or medicinal response that is being sought in a tissue,system, animal, individual or human by a researcher, veterinarian,medical doctor or other clinician.

In certain embodiments, a therapeutically effective amount can be anamount suitable for (1) preventing the disease; for example, preventinga disease, condition or disorder in an individual who may be predisposedto the disease, condition or disorder but does not yet experience ordisplay the pathology or symptomatology of the disease;

(2) inhibiting the disease; for example, inhibiting a disease, conditionor disorder in an individual who is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder; or

(3) ameliorating the disease; for example, ameliorating a disease,condition or disorder in an individual who is experiencing or displayingthe pathology or symptomatology of the disease, condition or disorder(i.e., reversing the pathology and/or symptomatology) such as decreasingthe severity of disease.

As used here, the terms “treatment” and “treating” means (i)ameliorating the referenced disease state, for example, ameliorating adisease, condition or disorder in an individual who is experiencing ordisplaying the pathology or symptomatology of the disease, condition ordisorder (i.e., reversing or improving the pathology and/orsymptomatology) such as decreasing the severity of disease; or (ii)eliciting the referenced biological effect (e.g., IDO modulation ortryptophan degradation inhibition).

Manifestation of amelioration of a disease condition with underlyingIDO-mediated immunosuppression may require the concomitant or sequentialadministration of additional therapeutic agents, such as antineoplasticagents in the case of cancer, or antiretroviral agents in the case ofviral diseases. For example, administration of IDO inhibitors for thetreatment of cancer does not always produce a direct antitumor effectwhen used as a single agent. However, when combined withchemotherapeutic drugs (antineoplastic) the antitumor effect observed ishigher than the sum of effects of each agent alone.

As used herein, the terms “catalytic pocket”, “catalytic site”, “activesite” collectively and indistinctly refer to a region of the enzyme thatcontains amino acid residues responsible for the substrate binding(charge, hydrophobicity, steric hindrance) and catalytic amino acidresidues which act as proton donors or acceptors or are responsible forbinding a cofactor and participate in the catalysis of a chemicalreaction.

As used herein, the phrase “pharmaceutically acceptable salt” refers toboth pharmaceutically acceptable acid and base addition salts andsolvates. Such pharmaceutically acceptable salts include salts of acidssuch as hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic,formic, toluenesulfonic, methanesulfonic, nitric, benzoic, citric,tartaric, maleic, hydroiodic, alkanoic such as acetic,HOOC—(CH₂)_(n)—COOH where n is 0-4, and the like. Non-toxicpharmaceutical base addition salts include salts of bases such assodium, potassium, calcium, ammonium, and the like. Those skilled in theart will recognize a wide variety of non-toxic pharmaceuticallyacceptable addition salts.

Methods of Use

The compounds and pharmaceutical compositions described herein canmodulate activity of the enzyme indoleamine-2,3-dioxygenase (IDO). Theterm “modulate” is meant to refer to an ability to decrease activity ofan enzyme or receptor. Accordingly, compounds described herein can beused in methods of modulating IDO by contacting the enzyme with any oneor more of the compounds or compositions described herein. In someembodiments, the compounds described herein can act as inhibitors ofIDO. In further embodiments, the compounds described herein can be usedto modulate activity of IDO in cell or in an individual in need ofmodulation of the enzyme by administering a modulating (e.g.,inhibiting) amount of a compound described herein.

Further provided are methods of inhibiting the degradation of tryptophanand preventing the production of N-formylkynurenine in a systemcontaining cells expressing IDO such as a tissue, living organism, orcell culture. In some embodiments methods of altering (e.g., increasing)extracellular tryptophan levels in a mammal comprise administering aneffective amount of a compound or pharmaceutical composition providedherein. Methods of measuring tryptophan levels and tryptophandegradation are routine in the art.

Further provided are methods of inhibiting immunosuppression such asIDO-mediated immunosuppression in a patient by administering to thepatient an effective amount of a compound or composition recited herein.IDO-mediated immunosuppression has been associated with, for example,cancers, tumor growth, metastasis, infectious diseases (e.g., viralinfection), viral replication, etc.

Further provided are methods for treating tumor-specificimmunosuppression associated with cancer in a patient by administeringto the patient an effective amount of a compound or composition recitedherein. Example tumor-specific immunosuppression associated with cancerstreatable by the methods herein include immunosuppression associatedwith cancer of the colon, pancreas, breast, prostate, lung, brain,ovary, cervix, testes, renal, head and neck, lymphoma, leukemia,melanoma, and the like.

For example, a patient undergoing or having completed a course ofchemotherapy and/or radiation therapy for the treatment of a diseasestate, such as a cancer, can benefit from administering to the patient atherapeutically effective amount of a compound or composition recitedherein for inhibiting immunosuppression resulting from the disease stateand/or treatment thereof.

Further provided are methods for treating immunosupression associatedwith an infectious disease, e.g., HIV-1 infection, in a patient byadministering to the patient an effective amount of a compound orcomposition recited herein.

For example, IDO-mediated immunosuppression associated with viralinfection, is associated with a viral infection selected from the groupconsisting of: influenza, hepatitis C virus (HCV), human papilloma virus(HPV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), poliovirus,varicella zoster virus, coxsackie virus, human immunodeficiency virus(HIV).

Further provided are methods of treating diseases associated withactivity or expression, including abnormal activity and/oroverexpression, of IDO in an individual (e.g., patient) by administeringto the individual in need of such treatment a therapeutically effectiveamount or dose of a compound described herein or a pharmaceuticalcomposition thereof. Example diseases can include any disease, disorderor condition that is directly or indirectly linked to expression oractivity of the IDO enzyme, such as over expression or abnormalactivity. An IDO-associated disease can also include any disease,disorder or condition that can be prevented, ameliorated, or cured bymodulating enzyme activity.

Examples of IDO-associated diseases include cancer, viral infection suchas HIV infection, depression, neurodegenerative disorders such asAlzheimer's disease and Huntington's disease, trauma, age-relatedcataracts, organ transplantation (e.g., organ transplant rejection), andautoimmune diseases including asthma, rheumatoid arthritis, multiplesclerosis, inflammatory bowel disease, psoriasis and systemic lupuserythematosusor. Example cancers treatable by the methods herein includecancer of the colon, pancreas, breast, prostate, lung, brain, ovary,cervix, testes, renal, head and neck, lymphoma, leukemia, melanoma, andthe like.

Combination Therapy

One or more additional pharmaceutical agents for treatment methods suchas, for example, anti-viral agents, chemotherapeutics or otheranti-cancer agents, immune enhancers, immunosuppressants, radiation,anti-tumor and anti-viral vaccines, cytokine therapy (e.g., IL2, GM-CSF,etc.), and/or tyrosine kinase inhibitors can be used in combination withthe compounds and pharmaceutical compositions described herein fortreatment of IDO-associated diseases, disorders or conditions (as notedabove) or for enhancing the effectiveness of the treatment of a diseasestate or condition, such as cancer. The agents can be combined with thepresent compounds in a single dosage form, or the agents can beadministered simultaneously or sequentially as separate dosage forms.

Therapeutic agents that constitute the standard of care for a particularcancer type or infectious disease are expected to benefit when combinedwith IDO inhibitors of the present invention. For example, for the caseof tumors, is it preferable that the tumor is sensitive to the cytotoxiceffects of the chemotherapeutic agent in order to stimulate the releaseof antigens that will eventually mediate an immune response that will beenhanced by addition of IDO inhibitors to the combination treatment. Aperson of skill in the art will know how to select such chemotherapeuticagent based on the clinical characteristics and known sensititivity ofeach tumor to different antineoplastic agents.

Suitable antiviral agents contemplated for use in combination with thecompounds described herein can comprise nucleoside and nucleotidereverse transcriptase inhibitors (NRTIs), non-nucleoside reversetranscriptase inhibitors (NNRTIs), protease inhibitors and otherantiviral drugs.

Example suitable NRTIs include zidovudine (AZT); didanosine (ddI);zalcitabine (ddC); stavudine (d4T); lamivudine (3TC); abacavir(1592U89); adefovir dipivoxil [bis(POM)-PMEA]; lobucavir (BMS-180194);BCH-10652; emitricitabine [(−)-FTC]; beta-L-FD4 (also called beta-L-D4Cand named beta-L-2′,3′-dicleoxy-5-fluoro-cytidene); DAPD,((−)-beta-D-2,6,-diamino-purine dioxolane); and lodenosine (FddA).Typical suitable NNRTIs include nevirapine (BI-RG-587); delaviradine(BHAP, U-90152); efavirenz (DMP-266); PNU-142721; AG-1549; MKC-442(1-(ethoxy-methyl)-5-(1-methylethyl)-6-(phenylmethyl)-(2,4(1H,3H)-pyrimidinedione);and (+)-calanolide A (NSC-675451) and B. Typical suitable proteaseinhibitors include saquinavir (Ro 31-8959); ritonavir (ABT-538);indinavir (MK-639); nelfnavir (AG-1343); amprenavir (141W94); lasinavir(BMS-234475); DMP-450; BMS-2322623; ABT-378; and AG-1549. Otherantiviral agents include hydroxyurea, ribavirin, IL-2, IL-12,pentafuside and Yissum Project No. 11607.

Suitable chemotherapeutic or other anti-cancer agents include, forexample, alkylating agents (including, without limitation, nitrogenmustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas andtriazenes) such as uracil mustard, chlormethine, cyclophosphamide(Cytoxan™), ifosfamide, melphalan, chlorambucil, pipobroman,triethylene-melamine, triethylenethiophosphoramine, busulfan,carmustine, lomustine, streptozocin, dacarbazine, and temozolomide.

Suitable chemotherapeutic or other anti-cancer agents include, forexample, antimetabolites (including, without limitation, folic acidantagonists, pyrimidine analogs, purine analogs and adenosine deaminaseinhibitors) such as methotrexate, 5-fluorouracil, floxuridine,cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate,pentostatine, and gemcitabine.

Suitable chemotherapeutic or other anti-cancer agents further include,for example, certain natural products and their derivatives (forexample, vinca alkaloids, antitumor antibiotics, enzymes, lymphokinesand epipodophyllotoxins) such as vinblastine, vincristine, vindesine,bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin,idarubicin, ara-C, paclitaxel (Taxol™), docetaxel, mithramycin,deoxyco-formycin, mitomycin-C, L-asparaginase, interferons (especiallyIFN-a), etoposide, and teniposide.

Other cytotoxic agents include navelbene, CPT-11, anastrazole,letrazole, capecitabine, reloxafine, cyclophosphamide, ifosamide, anddroloxafine.

Also suitable are cytotoxic agents such as epidophyllotoxin; anantineoplastic enzyme; a topoisomerase inhibitor; procarbazine;mitoxantrone; platinum coordination complexes such as cis-platin andcarboplatin; biological response modifiers; growth inhibitors;antihormonal therapeutic agents; leucovorin; tegafur; and haematopoieticgrowth factors.

Other anti-cancer agent(s) include antibody therapeutics such astrastuzumab (Herceptin), antibodies to costimulatory molecules such asCTLA-4,4-1BB and PD-1, or antibodies to cytokines (IL-10, TGF-β, etc.).

Other anti-cancer agents also include those that block immune cellmigration such as antagonists to chemokine receptors, including CCR2,CCR4 and CCR6.

Other anti-cancer agents also include those that augment the immunesystem such as adjuvants or adoptive T cell transfer.

Anti-cancer vaccines include dendritic cells, synthetic peptides, DNAvaccines and recombinant viruses.

Methods for the safe and effective administration of most of thesechemotherapeutic agents are known to those skilled in the art. Inaddition, their administration is described in the standard literature.For example, the administration of many of the chemotherapeutic agentsis described in the “Physicians' Desk Reference” (PDR, e.g., 1996edition, Medical Economics Company, Montvale, N.J.), the disclosure ofwhich is incorporated herein by reference as if set forth in itsentirety.

Pharmaceutical Formulations and Dosage Forms

The pharmaceutical compositions described herein generally comprise acombination of a compound described herein and a pharmaceuticallyacceptable carrier, diluent, or excipient. Such compositions aresubstantially free of non-pharmaceutically acceptable components, i.e.,contain amounts of non-pharmaceutically acceptable components lower thanpermitted by US regulatory requirements at the time of filing thisapplication. In some embodiments of this aspect, if the compound isdissolved or suspended in water, the composition further optionallycomprises an additional pharmaceutically acceptable carrier, diluent, orexcipient. In other embodiments, the pharmaceutical compositionsdescribed herein are solid pharmaceutical compositions (e.g., tablet,capsules, etc.).

These compositions can be prepared in a manner well known in thepharmaceutical art, and can be administered by a variety of routes,depending upon whether local or systemic treatment is desired and uponthe area to be treated. Administration may be topical (includingophthalmic and to mucous membranes including intranasal, vaginal andrectal delivery), pulmonary (e.g., by inhalation or insufflation ofpowders or aerosols, including by nebulizer; intratracheal, intranasal,epidermal and transdermal), ocular, oral or parenteral. Methods forocular delivery can include topical administration (eye drops),subconjunctival, periocular or intravitreal injection or introduction byballoon catheter or ophthalmic inserts surgically placed in theconjunctival sac. Parenteral administration includes intravenous,intraarterial, subcutaneous, intraperitoneal or intramuscular injectionor infusion; or intracranial, e.g., intrathecal or intraventricular,administration. Parenteral administration can be in the form of a singlebolus dose, or may be, for example, by a continuous perfusion pump.Pharmaceutical compositions and formulations for topical administrationmay include transdermal patches, ointments, lotions, creams, gels,drops, suppositories, sprays, liquids and powders. Conventionalpharmaceutical carriers, aqueous, powder or oily bases, thickeners andthe like may be necessary or desirable.

Also, pharmaceutical compositions can contain, as the active ingredient,one or more of the compounds described herein above in combination withone or more pharmaceutically acceptable carriers. In making thecompositions described herein, the active ingredient is typically mixedwith an excipient, diluted by an excipient or enclosed within such acarrier in the form of, for example, a capsule, sachet, paper, or othercontainer. When the excipient serves as a diluent, it can be a solid,semi-solid, or liquid material, which acts as a vehicle, carrier ormedium for the active ingredient. Thus, the compositions can be in theform of tablets, pills, powders, lozenges, sachets, cachets, elixirs,suspensions, emulsions, solutions, syrups, aerosols (as a solid or in aliquid medium), ointments containing, for example, up to 10% by weightof the active compound, soft and hard gelatin capsules, suppositories,sterile injectable solutions, and sterile packaged powders.

In preparing a formulation, the active compound can be milled to providethe appropriate particle size prior to combining with the otheringredients. If the active compound is substantially insoluble, it canbe milled to a particle size of less than 200 mesh. If the activecompound is substantially water soluble, the particle size can beadjusted by milling to provide a substantially uniform distribution inthe formulation, e.g. about 40 mesh.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. Theformulations can additionally include: lubricating agents such as talc,magnesium stearate, and mineral oil; wetting agents; emulsifying andsuspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents. Thecompositions described herein can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

The compositions can be formulated in a unit dosage form, each dosagecontaining from about 5 to about 100 mg, more usually about 10 to about30 mg, of the active ingredient. The term “unit dosage forms” refers tophysically discrete units suitable as unitary dosages for human subjectsand other mammals, each unit containing a predetermined quantity ofactive material calculated to produce the desired therapeutic effect, inassociation with a suitable pharmaceutical excipient.

The active compound can be effective over a wide dosage range and isgenerally administered in a pharmaceutically effective amount. It willbe understood, however, that the amount of the compound actuallyadministered will usually be determined by a physician, according to therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms, and the like.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound described herein. When referring to these preformulationcompositions as homogeneous, the active ingredient is typicallydispersed evenly throughout the composition so that the composition canbe readily subdivided into equally effective unit dosage forms such astablets, pills and capsules. This solid preformulation is thensubdivided into unit dosage forms of the type described above containingfrom, for example, 0.1 to about 500 mg of the active ingredient of acompound described herein.

The tablets or pills can be coated or otherwise compounded to provide adosage form affording the advantage of prolonged action. For example,the tablet or pill can comprise an inner dosage and an outer dosagecomponent, the latter being in the form of an envelope over the former.The two components can be separated by an enteric layer which serves toresist disintegration in the stomach and permit the inner component topass intact into the duodenum or to be delayed in release. A variety ofmaterials can be used for such enteric layers or coatings, suchmaterials including a number of polymeric acids and mixtures ofpolymeric acids with such materials as shellac, cetyl alcohol, andcellulose acetate.

The liquid forms in which the compounds and compositions can beincorporated for administration orally or by injection include aqueoussolutions, suitably flavored syrups, aqueous or oil suspensions, andflavored emulsions with edible oils such as cottonseed oil, sesame oil,coconut oil, or peanut oil, as well as elixirs and similarpharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. In some embodiments, the compositions are administered by theoral or nasal respiratory route for local or systemic effect.Compositions in can be nebulized by use of inert gases. Nebulizedsolutions may be breathed directly from the nebulizing device or thenebulizing device can be attached to a face masks tent, or intermittentpositive pressure breathing machine. Solution, suspension, or powdercompositions can be administered orally or nasally from devices whichdeliver the formulation in an appropriate manner.

The amount of compound or composition administered to a patient willvary depending upon what is being administered, the purpose of theadministration, such as prophylaxis or therapy, the state of thepatient, the manner of administration, and the like. In therapeuticapplications, compositions can be administered to a patient alreadysuffering from a disease in an amount sufficient to cure or at leastpartially arrest the symptoms of the disease and its complications.Effective doses will depend on the disease condition being treated aswell as by the judgment of the attending clinician depending uponfactors such as the severity of the disease, the age, weight and generalcondition of the patient, and the like.

The compositions administered to a patient can be in the form ofpharmaceutical compositions described above. These compositions can besterilized by conventional sterilization techniques, or may be sterilefiltered. Aqueous solutions can be packaged for use as is, orlyophilized, the lyophilized preparation being combined with a sterileaqueous carrier prior to administration. The pH of the compoundpreparations typically will be between 3 and 11, more preferably from 5to 9 and most preferably from 7 to 8. It will be understood that use ofcertain of the foregoing excipients, carriers, or stabilizers willresult in the formation of pharmaceutical salts.

The therapeutic dosage of the compounds can vary according to, forexample, the particular use for which the treatment is made, the mannerof administration of the compound, the health and condition of thepatient, and the judgment of the prescribing physician. The proportionor concentration of a compound described herein in a pharmaceuticalcomposition can vary depending upon a number of factors includingdosage, chemical characteristics (e.g., hydrophobicity), and the routeof administration. For example, the compounds described herein can beprovided in an aqueous physiological buffer solution containing about0.1 to about 10% w/v of the compound for parenteral administration. Sometypical dose ranges are from about 1 μg/kg to about 1 g/kg of bodyweight per day. In some embodiments, the dose range is from about 0.01mg/kg to about 100 mg/kg of body weight per day. The dosage is likely todepend on such variables as the type and extent of progression of thedisease or disorder, the overall health status of the particularpatient, the relative biological efficacy of the compound selected,formulation of the excipient, and its route of administration. Effectivedoses can be extrapolated from dose-response curves derived from invitro or animal model test systems.

The compounds described herein can also be formulated in combinationwith one or more additional active ingredients which can include anypharmaceutical agent such as anti-viral agents, vaccines, antibodies,immune enhancers, immune suppressants, anti-inflammatory agents and thelike.

Labeled Compounds and Assay Methods

Another aspect relates to fluorescent dye, spin label, heavy metal orradio-labeled derivatives of the compounds described herein that wouldbe useful not only in imaging but also in assays, both in vitro and invivo, for localizing and quantitating the IDO enzyme in tissue samples,including human, and for identifying IDO enzyme ligands by inhibitionbinding of a labeled compound. Accordingly, further provided are IDOenzyme assays that contain such labeled compounds.

Further provided are isotopically-labeled compounds of the compoundsdescribed herein. An “isotopically” or “radio-labeled” compound is acompound described herein where one or more atoms are replaced orsubstituted by an atom having an atomic mass or mass number differentfrom the atomic mass or mass number typically found in nature (i.e.,naturally occurring). Suitable radionuclides that may be include but arenot limited to 2H (also written as D for deuterium), 3H (also written asT for tritium), ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ¹⁸F, ³⁵S, ³⁶Cl,⁸²Br, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br, ¹²³I, ¹²⁴I, ¹²⁵I and ¹³¹I. The radionuclide thatis incorporated in the instant radio-labeled compounds will depend onthe specific application of that radio-labeled compound. For example,for in vitro IDO enzyme labeling and competition assays, compounds thatincorporate ³H, ¹⁴C, ⁸²Br, ¹²⁵I, ¹³¹I, ³⁵S or will generally be mostuseful. For radio-imaging applications ¹¹C, ¹⁸F, ¹²⁵I, ¹²³I, ¹²⁴I, ¹³¹I,⁷⁵Br, ⁷⁶Br Or ⁷⁷Br will generally be most useful.

It is understood that a “radio-labeled” or “labeled compound” is acompound that has incorporated at least one radionuclide. In someembodiments the radionuclide is selected from the group consisting of³H, ¹⁴C, ¹²⁵I, ³⁵S and ⁸²Br.

Synthetic methods for incorporating radio-isotopes into organiccompounds are applicable to compounds described herein and are wellknown in the art.

A radio-labeled compound described herein can be used in a screeningassay to identify/evaluate compounds. In general terms, a newlysynthesized or identified compound (i.e., test compound) can beevaluated for its ability to reduce binding of the radio-labeledcompound described herein to the IDO enzyme. Accordingly, the ability ofa test compound to compete with the radio-labeled compound for bindingto the IDO enzyme directly correlates to its binding affinity.

Kits

Also included are pharmaceutical kits useful, for example, in thetreatment or prevention of IDO-associated diseases or disorders,obesity, diabetes and other diseases referred to herein which includeone or more containers containing a pharmaceutical compositioncomprising a therapeutically effective amount of a compound describedherein. Such kits can further include, if desired, one or more ofvarious conventional pharmaceutical kit components, such as, forexample, containers with one or more pharmaceutically acceptablecarriers, additional containers, etc., as will be readily apparent tothose skilled in the art. Instructions, either as inserts or as labels,indicating quantities of the components to be administered, guidelinesfor administration, and/or guidelines for mixing the components, canalso be included in the kit.

The following examples are offered for illustrative purposes, and arenot intended to limit the disclosure in any manner. Those of skill inthe art will readily recognize a variety of noncritical parameters whichcan be changed or modified to yield essentially the same results. Theexample compounds below were found to be inhibitors of IDO according toone or more of the assays described herein.

EXAMPLES

All reagents and solvents were purchased from commercial sources. Allcommercial reagents and solvents were used as received without furtherpurification. The reactions were monitored using analytical thin layerchromatography (TLC) with 0.25 mm EM Science silica gel plates(60F-254). The developed TLC plates were visualized by short wave UVlight (254 nm) or immersion in potassium permanganate solution followedby heating on a hot plate. Flash chromatography was performed withSelecto Scientific silica gel, 32-63 μm particle sizes. All reactionswere performed in flame or oven-dried glassware under a nitrogenatmosphere. All reactions were stirred magnetically at ambienttemperature unless otherwise indicated. ¹H NMR spectra were obtainedwith a Bruker DRX400, Varian VXR400 or VXR300. ¹H NMR spectra werereported in parts per million (δ) relative to TMS (0.0), DMSO-d₆ (2.50)or CD₃OD (4.80) as an internal reference. All ¹H NMR spectra were takenin CDCl₃ unless otherwise indicated. The following starting materialswere prepared according to their literature procedures: (E)-ethyl3-(2-iodophenyl)acrylate (Synth. Comm. 2007, 37, 2989-2994),2-chloro-6-iodobenzaldehyde (J. Agric. Food Chem. 2008, 56, 5247-5253),2-iodo-3-methoxybenzaldehyde (Chem.-Eur. J., 2004, 10, 5233-5242),dimethyl (2-(cyclohex-1-en-1-yl)-2-oxoethyl)phosphonate (Phosphorus,Sulfur Silicon Relat. Elem., 1999, 155, 67-80), dimethyl(2-cyclohexyl-2-oxo)ethylphosphonate (Patent: U.S. Pat. No. 5,807,892A1, 1998), ethyl 1,4-dioxaspiro[4.5]decane-8-carboxylate (Patent:US2008/306084 A1, 2008), (trans)-ethyl4-((tert-butyldimethylsilyl)oxy)cyclohexanecarboxylate (Patent:US2006/25383 A1, 2006), ethyl spiro[2.5]octane-6-carboxylate (Bioorg.Med. Chem. Lett. 2008, 18, 5280-5284), ethyl4-(cyclopropylmethylene)cyclohexanecarboxylate (Patent: U.S. Pat. No.4,584,013 A1, 1986),

The aforementioned compounds are assigned compound identificationnumbers 86-91 and 113-115 respectively for future reference in thispatent. (4.80) as an internal reference. All spectra are recorded inCDCl₃ unless otherwise indicated.

A variety of methods used in this patent to synthesize intermediate Aare outlined below in Scheme 1. Palladium-catalyzed Suzukicross-coupling of 4-iodo-1-trityl-1H-imidazole with phenylboronic acidsgives rise to 2-(1-trityl-1H-imidazol-4-yl)benzaldehydes. The resulting2-(1-trityl-1H-imidazol-4-yl)benzaldehydes are affected by aldolcondensations or Horner-Wadsworth reactions to afford intermediate A.Alternatively, the synthesis of intermediate A can be achieved byallowing 2-iodobenzaldehydes to react with substituted methyl ketones inthe presence of a base to afford 3-(2-iodophenyl)prop-2-en-1-ones.Negishi cross-coupling of the resulting 3-(2-iodophenyl)prop-2-en-1-oneswith 4-iodo-1-trityl-1H-imidazole, also leads to intermediate A.Subjecting intermediate A to trityl deprotection conditions gives riseto 2-(5H-imidazo[5,1-a]isoindol-5-yl)ethanone B, which may be reduced to2-(5H-imidazo[5,1-a]isoindol-5-yl)ethanol C (Scheme 2).

Example 1 General Procedure for the Synthesis of3-(2-Iodophenyl)prop-2-en-1-ones by Aldol Condensation

To a solution of the appropriate commercially available benzaldehyde or87 (4.31 mmol) in anhydrous MeOH (15 mL) at rt was added NaOMe (4.31mmol, 0.5 M in MeOH) and the yellow solution was allowed to stir for 5min. The appropriate ketone (4.31 mmol) was added dropwise as a solutionin MeOH (3 mL). After stirring overnight, the solvent was removed underreduced pressure and the crude was diluted with satd. NH₄Cl (20 mL). Theaqueous layer was extracted with CH₂Cl₂(3×20 mL) and the combinedorganic extracts were dried (MgSO₄) and the solvent distilled off underreduced pressure to afford a crude residue. The crude product waspurified by silica flash chromatography to afford the followingcompounds.

# Compound Name Yield (%) 1

(E)-3-(2-chloro-6-iodophenyl)-1- cyclohexylprop-2-en-1-one 63 ¹H NMR1.22-1.45 (m, 5 H), 1.70-1.74 (m, 1H), 1.79-1.85 (m, 2H), 1.93-1.99 (m,2H), 2.61-2.65 (m, 1H), 6.67 (d, 1H, J = 16 Hz), 6.93 (t, 1H, J = 8 Hz),7.41 (d, 1H, J = 8 Hz), 7.48 (d, 1H, J = 16 Hz), 7.82 (d, 1H, J = 8 Hz)2

(E)-3-(2-iodophenyl)-1-(3-nitrophenyl)prop- 2-en-1-one 53 ¹H NMR7.10-7.16 (m, 1H), 7.34 (d, 1H, J = 15.6 Hz), 7.41-7.46 (m, 1H),7.71-7.76 (m, 2H), 7.94-7.97 (m, 1H), 8.05 (d, 1H, J = 15.6 Hz),8.34-8.48 (m, 2H), 8.81 (s, 1H)

Example 2 General Procedure for the Synthesis of2-(5H-imidazo[5,1-a]isoindol-5-yl)ethanones by Palladium-CatalyzedNegishi Cross-Coupling of Aryl Iodides 1 and 2 with4-Iodo-1-Trityl-1H-imidazole

To a stirred solution of 4-iodo-1-trityl-1H-imidazole (218 mg, 0.5 mmol)in anhydrous THF (4 mL) at rt was added EtMgBr (1.0 M in THF, 0.5 mmol,0.5 mL) dropwise, under an atmosphere of N₂. The resulting solution wasallowed to stir for 90 min and anhydrous ZnCl₂ (0.5 mmol, 68.2 mg) wasadded. The resulting white suspension was allowed to stir for 90 min anda solution of the appropriate aryl iodide 1, 2 or 86 (0.5 mmol) in THF(1 mL) was added followed by the immediate addition of Pd(PPh₃)₄ (56 mg,0.05 mmol). The reaction mixture was allowed to stir at 70° C. for 12 hunder an atmosphere of N₂. After cooling to room temperature, thesolution was diluted with CH₂Cl₂ (20 mL) and the organic layer waswashed with an EDTA (aq) buffer (pH=9) (2×5 mL) and brine. The organiclayer was dried (Na₂SO₄) and concentrated under reduced pressure. Thecrude residue was used in next step without further purification. To asolution of the crude imidazole from the previous step was added aceticacid (1.0 mL) and MeOH (4.0 mL). The solution was stirred at 90° C. for3 h. The reaction mixture was allowed to cool to room temperature andthe pH was adjusted to ˜10 with satd. K₂CO₃ (acq). The aqueous phase wasextracted with EtOAc (3×20 mL). The combined organic layers were washedwith water, brine and dried. The solvent was removed in vacuo to affordthe crude residue, which was purified by flash column chromatography onsilica gel to afford the following compounds.

# Compound Name Yield (%) 1287

2-(6-chloro-5H-imidazo[5,1-a]isoindol-5- yl)-1-cyclohexylethanone 25 ¹HNMR 1.18-1.36 (m, 5H), 1.68-1.88 (m, 5H), 2.37-2.40 (m, 1H), 2.64 (dd,1H, J = 20.0 Hz, 10.0 Hz), 3.79 (dd, 1H, J = 16.0 Hz, 4.0 Hz), 5.70 (d,1H, J = 8.0 Hz), 7.17-7.20 (m, 2H), 7.32 (t, 1H, J = 8.0 Hz), 7.43 (d,1H, J = 8.0 Hz), 7.61 (s, 1H) 1256

ethyl 2-(5H-imidazo[5,1-a]isoindol-5- yl)acetate 23 ¹H NMR 1.31 (t, 3H,J = 7.5 Hz), 2.67 (dd, 1H, J = 20.0 Hz, 12.0 Hz), 3.07 (dd, 1H, J = 20.0Hz, 4.0 Hz), 4.25 (q, 2H, J = 6.0 Hz), 5.53 (dd, 1H, J = 12.0 Hz, 4.0Hz), 7.16 (s, 1H), 7.21-7.37 (m, 3H), 7.51 (d, 1H, J = 6.0 Hz), 7.75 (s,1H 1306

2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(3- nitrophenyl)ethanone 15 ¹H NMR3.49 (dd, 1H, J = 18.6 Hz, 9.6 Hz), 3.80 (dd, 2H, J = 18.3 Hz, 3.3 Hz),5.84 (dd, 1H, J = 3 Hz, 9.3 Hz), 7.26-7.32 (m, 1H), 7.38-7.49 (m, 2H),7.55-7.59 (m, 1H), 7.70-7.76 (m, 2H), 8.32 (d, 1H, J = 6 Hz), 8.46-8.50(m, 1H), 8.78 (s, 1H)

Example 3 Suzuki Cross-Coupling of 4-Iodo-1-trityl-1H-imidazole withPhenylboronic Acids

A suspension of 4-iodo-1-trytyl-1H-imidazole (6.88 mmol), theappropriate 2-formyl boronic acid derivative (10.31 mmol) and K₃PO₄(20.63 mmol) in N,N-dimethylformamide (30 mL) and water (6 mL) waspurged with nitrogen for 5 minutes, followed by the addition ofPd(PPh₃)₄ and the mixture was purged with nitrogen for another 5minutes. The reaction mixture was stirred at 90° C. for 16 h under anatmosphere of N₂. The solution was allowed to cool and was filteredthrough a plug of celite. The mixture was diluted with water (50 mL) andEtOAc (25 mL). The organic layer was collected and the aqueous layer wasextracted with EtOAc (2×25 mL). The combined organic extracts werewashed with water (2×25 mL), brine and dried (Na₂SO₄). The solution wasfiltered and the solvent was removed under reduced pressure to affordthe crude product which was purified by flash column chromatography onsilica gel to provide the following compounds.

# Compound Name Yield (%) 3

2-(1-trityl-1H-imidazol-4-yl)benzaldehyde 52 ¹H NMR7.03 (s, 1H),7.18-7.20 (m, 6 H), 7.36-7.39 (m, 10H), 7.53-7.58 (m, 3H), 7.64 (d, 1H,J = 7.78 Hz), 7.93 (d, 1H, J = 7.87 Hz) 4

2-fluoro-6-(1-trityl-1H-imidazol-4- yl)benzaldehyde 46 ¹H NMR7.02-7.07(m, 1H), 7.10 (d, 1H, J = 1.6 Hz), 7.16-7.18 (m, 6H), 7.36-7.39 (m, 9H),7.46-7.52 (m, 2H), 7.57 (s, 1H), 10.27 (s, 1H) 5

5-chloro-2-(1-trityl-1H-imidazol-4- yl)benzaldehyde 48 ¹H NMR7.04 (d,1H, J = 1.2 Hz), 7.10-7.19 (m, 5H), 7.32-7.38 (m, 12H), 7.58 (dd, 1H, J= 2.4, 8.4 Hz), 7.57-7.59 (m, 2H), 7.89 (d, 1H, J = 2.0 Hz), 10.34 (s,1H) 6

4-chloro-2-(1-trityl-1H-imidazol-4- yl)benzaldehyde 55 ¹H NMR7.08-7.38(m, 18 H), 7.60 (s, 1H), 7.88 (d, 1H, J = 8.4 Hz), 10.41 (s, 1H) 7

4-fluoro-2-(1-trityl-1H-imidazol-4- yl)benzaldehyde 89 ¹H NMR (MeOH-d₄)7.16-7.27 (m, 6H), 7.29-7.47 (m, 3H), 7.60-7.70 (m, 9H), 7.85- 7.90 (m,2H), 10.26 (s, 1H)

Example 4 3-Methoxy-2-(1-trityl-1H-imidazol-4-yl)benzaldehyde

A suspension of 88 (667 mg, 2.55 mmol), bis(pinacolato)diboron (711 mg,2.88 mmol), KOAc (749 mg, 7.64 mmol), Pd(OAc)₂ (17 mg, 76 μmol) in DMF(10 mL) was stirred at 80° C. for 16 h. The mixture was filtered througha plug of Celite and the filtrate poured into water. The aqueous layerwas extracted with EtOAc (2×30 mL). The combined organic extracts werewashed with water (2×10 mL), brine, dried and concentrated. The crudeproduct was used without further purification. A suspension of4-iodo-1-trityl-1H-imidazole (400 mg, 0.917 mmol),3-methoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde(288 mg, 1.10 mmol), K₂CO₃ (444 mg, 3.21 mmol), Pd(dppf)Cl₂.CH₂Cl₂complex (150 mg, 0.18 mmol) in DMSO (10 mL) was heated at 80° C. for 20h. The solution was filtered through Celite and the filtrate poured intowater. The aqueous layer was extracted with ethyl acetate (2×20 mL). Thecombined organic layers were washed with water (2×10 mL), brine, dried,and concentrated. The crude was purified by flash column chromatographyto afford 8 as a white solid (78 mg, 19%). ¹H NMR: 3.75 (s, 3H), 7.08(d, 1H, J=8.0 Hz), 7.20-7.25 (m, 7H), 7.30-7.36 (m, 10H), 7.52 (s, 1H),7.55 (d, 1H, J=4.0 Hz), 10.31 (s, 1H).

Example 5 General Procedure for the Synthesis of2-(5H-imidazo[5,1-a]isoindol-5-yl)ethanones by Aldol Condensation of2-(1-trityl-1H-imidazol-4-yl)benzaldehydes with Methyl Ketones Followedby Cyclization

To a solution of the appropriate aldehyde 3-8 (0.97 mmol) and ketone(0.97 mmol) in anhydrous THF (5 mL) at rt was added NaOEt (1.25 mmol, 21wt % solution in EtOH) and the yellow solution was allowed to stir 3 hat rt. The solvent was distilled off and the crude was diluted withsaturated NH₄Cl (10 mL) and the aqueous layer was extracted withdichloromethane (3×20 mL). The combined organic extracts were washedwith brine, dried over Na₂SO₄ and the solvent evaporated under reducedpressure to afford the crude product. To the crude imidazole from theprevious step was added acetic acid (1.0 mL) and MeOH (4.0 mL). Thesolution was stirred at 90° C. for 3-10 h. The reaction mixture wasallowed to cool to room temperature and the pH was adjusted to ˜10 withsatd. K₂CO₃ (aq). The aqueous phase was extracted with EtOAc (3×20 mL).The combined organic layers were washed with water, brine, and dried.The solvent was removed in vacuo to afford the crude residue, which waspurified by flash column chromatography on silica gel to afford thefollowing compounds.

# Compound Name Yield (%) 1326

2-(5H-imidazo[5,1-a]isoindol-5- yl)-1-(2-nitrophenyl)ethanone 16 ¹H NMR3.19 (dd, 1H, J = 20.0 Hz, 8.0 Hz), 3.65 (dd, 1H, J = 20.0 Hz, 4.0 Hz),5.81 (dd, 1H, J = 8.0 Hz, 4.0 Hz), 7.19 (s, 1H), 7.22-7.28 (m, 1H), 7.36(m, 3H), 7.54 (d, 1H, J = 8.0 Hz), 7.61-7.65 (m, 1H), 7.70-7.74 (m, 1H),7.85 (s, 1H), 8.16 (d, 1H, J = 8.0 Hz). 1328

tert-butyl (2-(2-(5H-imidazo[5,1- a]isoindol-5-yl)acetyl)phenyl)carbamate 44 ¹H NMR 1.50 (s, 9H), 3.47 (dd, 1H, J =18.0 Hz, 9.6 Hz), 3.77 (dd, 1H, 18.0 Hz, 3.3 Hz), 5.77-5.81 (m, 1H),6.98 (t, 1H, J = 8.0 Hz), 7.19 (s, 1H), 7.28 (d, 1H, J = 7.6 Hz), 7.37(d, 1H, J = 8.0 Hz), 7.41 (d, 1H, J = 8.0 Hz), 7.52-7.56 (m, 2H), 7.72(d, 1H, J = 8.0 Hz), 7.77 (s, 1H), 8.54 (d, 1H, J = 8.4 Hz) 1300

tert-butyl (4-(2-(5H-imidazo[5,1- a]isoindol-5-yl)acetyl)phenyl)carbamate 39 ¹H NMR 1.52 (s, 9H), 3.39 (dd, 1H, J =18.6 Hz, 9.6 Hz), 3.68 (dd, 1H, J = 18.3 Hz, 3.3 Hz), 5.83 (dd, 1H, J =3 Hz, 9.3 Hz), 6.88 (s, 1H), 7.14-7.585 (m, 7H), 7.75 (s, 1H), 7.92 (d,2H, J = 9 Hz) 1348

2-(5H-imidazo[5,1-a]isoindol-5- yl)-1-phenylethanone 45 ¹H NMR 3.44 (dd,1H, J = 20.0 Hz, 8.0 Hz), 3.72 (dd, 1H, J = 20.0 Hz, 4.0 Hz), 5.83 (d,1H, J = 8.0 Hz), 7.18 (s, 1H), 7.25-7.29 (m, 1H), 7.40 (t, 2H, J = 10Hz), 7.47 (t, 2H, J = 8.0 Hz), 7.57 (d, 1H, J = 8.0 Hz), 7.61 (t, 1H, J= 6.0 Hz), 7.74 (s, 1H), 7.97 (d, 2H, J = 8 Hz) 9

tert-butyl 4-(2-(5H-imidazo[5,1- a]isoindol-5-yl)acetyl)piperidine-1-carboxylate 19 ¹H NMR 1.44 (s, 9H), 1.50-1.82 (m, 4H), 2.72-2.76 (m,2H), 2.90 (dd, 1H, J = 18.5 Hz, 9.4 Hz), 3.21 (dd, 1H, J = 18.57 Hz, 3.6Hz), 5.63 (dd, 1H, J = 9.6 Hz, 3.6 Hz), 7.16 (s, 1H), 7.23 (m, 2H),7.35-7.39 (m, 1H), 7.53 (d, 1H, J = 7.5 Hz), 7.59 (s, 1H) 10

2-(6-fluoro-5H-imidazo[5,1- a]isoindol-5-yl)-1-(1,4-dioxaspiro[4.5]decan-8- yl)ethanone 18 ¹H NMR (MeOH-d₄) 1.50-1.90 (m,6H), 2.35-2.60 (m, 2H), 2.98 (dd, 1H, J = 18.9 Hz, 10.2 Hz), 3.61 (dd,1H, J = 18.9 Hz, 2.7 Hz), 5.78-5.82 (m, 1H), 7.01-7.07 (m, 1H), 7.16 (s,1H), 7.42-7.45 (m, 2H), 7.66 (s, 1H) 11

2-(8-chloro-5H-imidazo[5,1- a]isoindol-5-yl)-1- cyclohexylethanone 21 ¹HNMR (MeOH-d₄) 1.10-1.90 (m, 10H), 2.42-2.48 (m, 1H), 2.99 (dd, 1H, J =18.9 Hz, 9 Hz), 3.40 (dd, 1H, J = 18.9 Hz, 3.6 Hz), 5.58-5.62 (m, 1H),6.95-7.08 (m, 1H), 7.16-7.88 (m, 4H) 12

2-(7-chloro-5H-imidazo[5,1- a]isoindol-5-yl)-1- cyclohexylethanone 43 ¹HNMR 1.19-1.46 (m, 5H), 1.68-1.70 (m, 1H), 1.78-1.91 (m, 5H), 2.35-2.43(m, 1H), 2.91 (dd, 1H, J = 10.0, 20.0 Hz), 3.18 (dd, 1H, J = 4.0, 20.0Hz), 5.611 (dd, 1H, J = 4.0, 8.0 Hz), 7.15 (s, 1H), 7.28 (s, 1H), 7.35(d, 1H, J = 8.0 Hz), 7.45 (d, 1H, J = 8.0 Hz), 7.60 (s, 1H) 13

1-cyclohexyl-2-(6-fluoro-5H- imidazo[5,1-a]isoindol-5- yl)ethanone 50 ¹HNMR 1.20-1.48 (m, 5H), 1.66-1.69 (m, 1H)1.78-1.92 (m, 5H), 2.36-2.44 (m,1H), 2.79 (dd, J = 12.0, 20.0 Hz), 3.50 (dd, 1H, J = 4.0, 20.0 Hz), 5.77(d, 1H, J = 8.0 Hz), 6.94 (t, 1H, J = 8.0 Hz), 7.18 (s, 1H), 7.31-7.37(m, 2H), 7.62 (s, 1H) 14

1-cyclohexyl-2-(9-methoxy-5H- imidazo[5,1-a]isoindol-5- yl)ethanone 41¹H NMR 1.32-1.42 (m, 2H), 1.66-1.69 (m, 1H), 1.78-1.90 (m, 4H),2.35-2.38 (m, 1H), 2.88 (dd, 1H, J = 18.4 Hz, 10 Hz), 3.17 (dd, 1H, J =13.8 Hz, 3.2 Hz), 3.96 (s, 3H), 5.60-5.64 (m, 1H), 6.88 (d, 2H, J = 8Hz), 7.15 (s, 1H), 7.21 (t, 1H, J = 8 Hz), 7.59 (s, 1H), 15

2-(5H-imidazo[5,1-a]isoindol-5- yl)-1-(tetrahydro-2H-pyran-4-yl)ethanone 61 ¹H NMR 1.75-1.84 (m, 4H), 2.58-2.62 (m, 1H), 2.90 (dd,1H, J = 18.4 Hz, 9.6 Hz), 3.21 (dd, 1H, J = 18.4 Hz, 3.6 Hz), 3.38-3.45(m, 2H), 3.99-4.01 (m, 2H), 5.65 (dd, 1H, J = 9.6 Hz, 3.6 Hz), 7.17 (s,1H), 7.22-7.30 (m, 2H), 7.38 (dt, 1H, J = 7.2 Hz, 0.8 Hz), 7.54 (d, 1H,J = 7.6 Hz), 7.61 (s, 1H) 16

1-cyclohexyl-2-(8-fluoro-5H- imidazo[5,1-a]isoindol-5- yl)ethanone 58 ¹HNMR a 17

tert-butyl (3-(2-(5H-imidazo[5,1- a]isoindol-5-yl)acetyl)phenyl)carbamate 80 ¹H NMR a 18

1-cyclopentyl-2-(5H-imidazo[5,1- a]isoindol-5-yl)ethanone 11 ¹H NMR a1334

1-(2-chlorophenyl-2-(5H- imidazo[5,1-a]isoindol-5- yl)ethanone 15 ¹H NMR3.30-3.50 (m, 1H), 3.65-3.85 (m, 1H), 5.50-5.70 (m, 1H), 7.17 (s, 1H),7.20- 7.60 (m, 8H), 7.75 (s, 1H) 1353

1-(3-chlorophenyl-2-(5H- imidazo[5,1-a]isoindol-5- yl)ethanone 20 ¹H NMR3.30-3.50 (m, 1H), 3.60-3.75 (m, 1H), 5.75-5.85 (m, 1H), 7.15 (s, H),7.20- 7.60 (m, 6H), 7.69 (s,1H), 7.82 (d, 1H, J = 10.4 Hz), 7.93(t, 1H,J = 2.4 Hz) a The compound was not characterized and was used as suchfor the next synthetic step

Example 6 Ethyl 4-methylenecyclohexanecarboxylate

To a suspension of methyltriphenylphosphonium bromide (1.57 g, 4.41mmol) in THF (9 mL) at −10° C. was added n-BuLi (2.5 M in hexanes, 1.65mL, 4.11 mmol) dropwise and the solution was allowed to stir for 1 h.Ethyl 4-oxocyclohexanecarboxylate (0.47 mL, 2.94 mmol) was added and thereaction was allowed to warm to room temperature over 3 h. Acetone (3mL) was added and the solvent was removed under reduced pressure. Theresidue was suspended in dichloromethane and ethyl ether (1:1), filteredand concentrated. The crude was purified by flash column chromatographyto afford 19 as clear oil (419 mg, 85%). ¹H NMR: 1.25 (t, 3H), 1.50-1.70(m, 2H), 1.90-2.16 (m, 4H), 2.30-2.50 (m, 3H), 4.12 (q, 2H), 4.65 (s,2H).

Example 7 Ethyl 4-(iodomethylene)cyclohexanecarboxylate

To a suspension of iodomethyltriphenylphosphonium iodide (1.95 g, 3.67mmol) in THF (10 mL) at −23° C. was slowly added a solution of potassiumhexamethyldisilazane (20% in toluene, 7.34 mL, 3.67 mmol) and theresulting solution was allowed to stir for 15 min. Ethyl4-oxocyclohexanecarboxylate (500 mg, 2.94 mmol) was added. The cold bathwas removed and the solution was allowed to stir at room temperature for2 days. The reaction mixture was diluted with water (20 mL) andextracted with ether (3×20 mL). The combined organic layers were driedover anhydrous MgSO₄ and concentrated to obtain the crude product. Thecrude residue was purified by column chromatography to obtain 20 aslight pink oil (207 mg, 24%). ¹H NMR: 1.21-1.52 (m, 2H), 1.93-2.13 (m,4H), 2.30-2.50 (m, 4H), 2.49-2.70 (m, 4H), 4.12 (q, 2H), 4.60 (s, 1H)

Example 8 Ethyl 4-(propan-2-ylidene)cyclohexanecarboxylate

To a suspension of isopropyltriphenylphosphonium iodide (3.81 g, 8.81mmol) in anhydrous THF (20 mL) at 0° C. was added a solution of t-BuOK(1.19 g, 10.58 mmol) in THF (15 mL). The reaction mixture was allowed towarm to rt and stirred for 1 h. The resulting mixture was cooled to 0°C., 4-Oxo-cyclohexanecarboxylic acid ethyl ester (1.0 g, 5.88 mmol) wasadded over a period of 5 min. The solution was allowed to slowly warm tort and stirred for 2 h. The solution was stirred at 50° C. overnight.The solvent was distilled off under reduced pressure and the crude waspartitioned between CH₂Cl₂ (50 mL) and satd. NH₄Cl (30 mL). The organiclayer was collected and the aqueous layer was extracted with CH₂Cl₂(2×30 mL). The organic layer was washed with brine, dried (Na₂SO₄) andconcentrated under reduced pressured to obtain the crude product. Thecrude was purified by column chromatography on silica gel to afford 21as a clear oil (280 mg, 24%). ¹H NMR: 1.24 (t, 3H, J=6.0 Hz), 1.43-1.50(m, 2H), 1.63 (s, 6H), 1.74-1.83 (m, 2H), 1.92-1.98 (m, 2H), 2.39-2.47(m, 1H), 2.58-2.69 (m, 2H).

Example 9 Ethyl 4-(cyclopropylmethylene)cyclohexanecarboxylate

To a suspension of cyclopropylmethyltriphenylphosphonium iodide (3.5 g,8.81 mmol) in anhydrous THF (20 mL) at 0° C. was added a solution oft-BuOK (1.19 g, 10.58 mmol) in THF (15 mL). The reaction mixture wasallowed to warm to rt and stirred for 1 h. The resulting mixture wascooled to 0° C., 4-Oxo-cyclohexanecarboxylic acid ethyl ester (1.0 g,5.88 mmol) was added over a period of 5 min. The solution was allowed toslowly warm to rt and stirred for 2 h. The solution was stirred at 50°C. overnight. The solvent was distilled off under reduced pressure andthe crude was partitioned between CH₂Cl₂ (50 mL) and satd. NH₄Cl (30mL). The organic layer was collected and the aqueous layer was extractedwith CH₂Cl₂ (2×30 mL). The organic layer was washed with brine, dried(Na₂SO₄) and concentrated under reduced pressured to obtain the crudeproduct. The crude was purified by column chromatography on silica gelto afford 22 as colorless oil (800 mg, 65%). ¹H NMR: CDCl₃ 0.22-0.26 (m,2H), 0.62-0.68 (m, 2H), 1.22 (t, 3H, J=7.2 Hz), 1.39-1.47 (m, 3H),1.75-2.04 (m, 4H), 2.14-2.20 (m, 1H), 2.37-2.46 (m, 1H), 2.67-2.75 (m,1H), 4.10 (q, 2H, J=7.2 Hz), 4.49 (d, 1H, J=9.3 Hz).

Example 10 Ethyl 4-(trityloxy)cyclohexanecarboxylate

To a solution of triphenylmethyl chloride (0.97 g, 3.48 mmol) indichloromethane (10 mL) was added DBU (0.61 mL, 4.06 mmol) and ethyl4-hydroxycyclohexanecarboxylate (500 mg, 2.90 mmol) and the mixture wasrefluxed for 24 h. The reaction mixture cooled and cold water (40 mL)was added. The organic layer was collected and the aqueous layer wasextracted with dichloromethane (2×30 ml). The combined organic layerswere dried (Na₂SO₄) and concentrated under reduced pressure. The crudewas purified by flash column chromatography to afford 23 as colorlessoil (714 mg, 59%). ¹HNMR: (mixture of cis and trans isomers (1:1.4))1.06 (t, 2H, J=12.4 Hz), 1.16-1.26 (m, 14H), 1.32-1.35 (m, 2H),1.54-1.58 (m, 2H), 1.76-1.79 (m, 3H), 1.95-2.04 (m, 2H), 2.11-2.22 (m,2H), 3.35-3.41 (m, 1.4H), 3.72-3.76 (m, 1H), 4.04 (q, 2.8H, J=7.2 Hz),4.14 (q, 2H, J=6.8 Hz), 7.22-7.27 (m, 24H, merged with CHCl₃), 7.49-7.51(m, 13H).

Example 11 Methyl cis-4-aminocyclohexanecarboxylate hydrochloride

A solution of cis-4-aminocyclohexanecarboxylic acid (1.04 g, 7.26 mmol)in 10 mL of methanol was cooled to 0° C. and thionyl chloride (1.58 mL,21.79 mmol) was added. The reaction mixture was warmed to RT and stirredfor 18 h. The reaction solution was concentrated, and the residue waswashed with ethyl ether to obtain 115 as colorless crystals (1.3 g,92%). ¹H NMR (CD₃OD): 1.73-1.77 (m, 4H), 1.92-1.96 (m, 2H), 2.16-2.73(m, 2H), 2.70-2.73 (m, 1H), 3.19-3.24 (m, 1H), 3.74 (s, 3H).

Example 12 Methyl cis-4-benzamidocyclohexanecarboxylate

To a suspension of methyl cis-4-aminocyclohexanecarboxylatehydrochloride (0.63 g, 3.26 mmol) in CH₂Cl₂ (10 mL) at 0° C. was addeddiisopropylethylamine (1.71 mL, 9.79 mmol) and the suspension wasstirred for 10 minutes. Benzoyl chloride (0.45 mL, 3.92 mmol) was addeddropwise and the clear solution was allowed to warm to rt and stirredovernight. The reaction was diluted with water (15 mL) and CH₂Cl₂(15mL), the organic layer was collected and the aqueous layer was extractedwith CH₂Cl₂ (2×25 mL). The combined organic extracts were dried overNa₂SO₄ and concentrated under reduce pressure to afford 116 as a cleargel (850 mg, 100%). ¹H NMR: 1.70-1.73 (m, 2H), 1.76-1.90 (m, 4H),1.95-2.06 (m, 2H), 2.55-2.61 (m, 1H), 3.72 (s, 3H), 4.14-4.20 (m, 1H),6.14 (d, 1H, J=6.0 Hz), 7.43-7.47 (m, 2H), 7.49-7.51 (m, 1H), 7.76-7.78(m, 2H).

Example 13 Methyl trans-4-aminocyclohexanecarboxylate hydrochloride

A solution of trans-4-aminocyclohexanecarboxylic acid (1.24 g, 8.66mmol) in 12 mL of methanol was cooled to 0° C. and thionyl chloride(1.89 mL, 25.98 mmol) was added. The reaction mixture was warmed to RTand stirred for 18 h. The reaction solution was concentrated, and theresidue was washed with ethyl ether to obtain 117 as colorless crystals(1.61 g, 95%). ¹H NMR (CD₃OD): 1.43-1.61 (m, 4H), 2.11-2.15 (m, 4H),2.39 (dt, 1H, J=2.8, 11.8 Hz), 3.12 (dt, 1H, J=3.2, 8.0 Hz), 3.70 (s,3H).

Example 14 Methyl trans-4-benzamidocyclohexanecarboxylate

To a suspension of methyl trans-4-aminocyclohexanecarboxylatehydrochloride, 9.79 mmol) and the suspension was stirred for 10 minutes.Benzoyl chloride (0.45 mL, 3.92 mmol) was added dropwise and the clearsolution was allowed to warm to rt and stirred overnight. The reactionwas diluted with water (15 mL) and CH₂Cl₂ (15 mL), the organic layer wasseparated and the aqueous layer was extracted with CH₂Cl₂ (2×25 mL). Thecombined organic extract was dried over Na₂SO₄ and concentrated underreduce pressure to afford 118 as a white solid (200 mg, 24%). ¹H NMR(CD₃OD): 1.46 (q, 2H, J=11.5 Hz), 1.60 (q, 2H, J=12.0 Hz), 2.09 (d, 4H,J=11.2 Hz), 2.37 (t, 1H, J=12.0 Hz), 3.71 (s, 3H), 3.90 (t, 1H, J=11.4Hz), 7.46-7.57 (m, 3H), 7.83 (d, 2H, J=7.1 Hz).

Example 15 1-tert-butyl 3-methyl azetidine-1,3-dicarboxylate

1-(t-butoxycarbonyl)azetidine-3-carboxylic acid (2.03 g, 10.09 mmol) wasdissolved in MeOH (10 ml) and DCM (10 mL) and then cooled to 0° C. A 2Msolution of trimethylsilyldiazomethane in ether (7.57 ml, 15.1 mmol) wasthen added drop-wise over 5 minutes. The solution was stirred for 10minutes at 0° C. and then warmed to room temperature over 30 minutes.The solution was concentrated under reduced pressure to remove volatilesto afford crude 119, which was used directly in the next step withoutfurther purification. ¹H NMR: 1.44 (s, 9H), 3.35 (m, 1H), 3.75 (s, 3H),4.10 (d, 4H, J=7.6 Hz).

Example 16 Methyl cis-4-hydroxycyclohexanecarboxylate

To a solution of cis-4-hydroxycyclohexanecarboxylic acid (5.0 g, 34.7mmol) in dry MeOH (40 mL) at RT, was added concentrated H₂SO₄ (0.2 mL,3.47 mmol) and the solution was stirred at 65° C. for 16 h. The solventwas distilled off and the crude was dissolved in EtOAc (40 mL) and thesolution was washed with sat'd NaHCO₃ solution (25 mL). The organiclayer was separated and the aqueous layer was extracted with EtOAc (2×20mL). The combined organic extracts were dried over Na₂SO₄ andconcentrated under reduced pressure to afford 120 (4.90 g, 89%). ¹H NMR:1.62-2.01 (m, 8H), 2.34-2.38 (m, 1H), 3.64 (s, 3H), 3.82-3.88 (m, 1H).

Example 17 Methyl cis-4-(benzyloxy)cyclohexanecarboxylate

To a solution of methyl cis-4-hydroxycyclohexanecarboxylate (4.80 g,30.3 mmol) in hexane/CHCl3 2:1 (60 mL) was added benzyltrichloroacetimidate (9.19 g, 36.4 mmol) and trifluoromethanesulfonicacid (683 mg, 4.55 mmol) at 23° C. The reaction mixture was stirred for18 h and diluted with EtOAc (300 mL). The mixture was washed withsaturated aqueous NaHCO3, water and brine. The organic layer was driedover anhydrous Na2SO4 and concentrated under reduced pressure. The crudereside was purified by column chromatography on silica gel to afford 121(4.60 g, 18.5 mmol). ¹H NMR: 1.55-1.98 (m, 8H), 2.36-2.41 (s, 1H),3.56-3.66 (, 1H), 3.67 (s, 3H), 4.51 (s, 2H), 7.28-7.35 (m, 5H).

Example 18 General Procedure for the Reaction of MethylPiperidine-4-carboxylate hydrochloride with Acid Chlorides

To a suspension of methyl piperidine-4-carboxylate hydrochloride (5.6mmol) in CH₂Cl₂ (20 mL) at 0° C. was added diisopropylethyl amine (16.7mmol) and the suspension was stirred for 10 minutes. Appropriate acidchloride (8.4 mmol) was added dropwise and the solution was allowed towarm to rt and stirred overnight. The reaction was diluted with water(15 mL) and CH₂Cl₂ (15 mL). The organic layer was collected and theaqueous layer was extracted with CH₂Cl₂ (2×20 mL). The combined organicextracts were dried (Na₂SO₄) and concentrated under reduce pressure toafford the following compounds.

# Compound Name Yield (%) 24

methyl 1-pivaloylpiperidine-4-carboxylate 77 ¹H NMR 1.21 (s, 9H)1.65-1.53 (m, 2H), 1.87-1.92 (m, 2H), 2.48-2.52 (m, 1H), 2.89-2.93 (m,2H), 3.63 (s, 3H), 4.18-4.22 (m, 1H), 4.24-4.27 (m, 1H) 25

methyl 1-(thiophene-2-carbonyl)piperidine-4-carboxylate 91 ¹H NMR1.69-1.79 (m, 2H), 1.89-1.95 (m, 2H), 2.56-2.63 (m, 1H), 3.12 (t, 2H, J= 12.0 Hz), 3.68 (s, 3H), 4.28-4.31 (m, 2H), 7.0-7.02 (m, 1H), 7.24-7.26(m, 1H), 7.40-7.42 (m, 1H) 26

methyl 1-(2-phenylacetyl)piperidine-4-carboxylate 44 ¹H NMR 1.30-1.95(m, 4H), 2.35-2.55(m, 1H), 2.70-2.85 (m, 1H), 2.95-3.10 (m, 1H), 3.62(s, 3H), 3.70 (s, 2H), 3.70-3.85 (m, 1H), 4.30-4.40 (m, 1H), 7.15-7.35(m, 5H)

Example 19 Methyl 2-bromo-3-fluorobenzoate

To a suspension of 2-bromo-3-fluorobenzoic acid (300 mg, 1.37 mmol) inmethanol (10 mL) at rt, was added SOCl₂ (0.11 mL, 1.51 mmol) and themixture was stirred at rt for 18 h. The solvent was distilled off underreduced pressure. The crude was basified by adding saturated aqueousNaHCO₃ solution and the aqueous layer was extracted with EtOAc (3×25mL). The combined organic layers were dried over Na₂SO₄, filtered andconcentrated. The obtained crude product was used in the next stepwithout further purification.

Example 20 Methyl 3-fluoro-2-(1-trityl-1H-imidazol-4-yl)benzoate

To a stirred solution of 4-iodo-1-trityl-1H-imidazole (436 mg, 1.0 mmol)in anhydrous THF (6 mL) was added EtMgBr (3.0 M in THF, 1.20 mmol, 0.40mL) under an atmosphere of N₂. The resulting solution was allowed tostir for 90 min and ZnCl₂ (0.5 M in THF, 2.40 mL, 1.20 mmol) was added.The resulting white suspension was allowed to stir for 90 min and asolution of methyl 2-bromo-3-fluorobenzoate (280 mg, 1.20 mmol) in THF(1 mL) was added followed by the immediate addition of Pd(PPh₃)₄ (58 mg,0.05 mmol). The reaction mixture was allowed to stir at 90° C. for 18 hunder an atmosphere of N₂. After cooling to room temperature, thesolution was diluted with CH₂Cl₂ (20 mL) and the organic layer waswashed with an EDTA (aq) buffer (pH=9) (2×5 mL) and brine. The organiclayer was dried (Na₂SO₄) and concentrated under reduced pressure. Thecrude residue was purified by flash column chromatography to afford thedesired product as yellow oil (190 mg, 41%). ¹H NMR: 3.93 (s, 3H),7.12-7.59 (m, 18H), 7.56 (s, 1H), 7.73-7.75 (m, 1H).

Example 21 3-Fluoro-2-(1-trityl-1H-imidazol-4-yl)benzaldehyde

To a solution of methyl 3-fluoro-2-(1-trityl-1H-imidazol-4-yl)benzoate(62 mg, 0.134 mmol) in toluene (4 mL) at −78° C. was added dropwise asolution DIBAH (1 M, 0.161 mL, 0.161 mmol) Stirring was continued at for10 min. At this temperature, dry methanol was added. The mixture waspoured into saturated aqueous NH₄Cl (5 mL), diluted with EtOAc (15 mL),shaken vigorously for 3 min, added brine (5 mL), shaken again, thephases separated and the organic layer dried over Na₂SO₄, filtered, andevaporated to give the desired aldehyde which was used without furtherpurification.

Example 22 General Procedure for the Synthesis of Dimethyl(2-oxo)phosphonates

To a stirred solution of dimethyl methylphosphonate (3.14 g, 25.3 mmol)in 20 ml of anhydrous tetrahydrofuran at −78° C. was added dropwise asolution of n-butyl lithium (10.13 mL, 25.3 mmol, 2.5 M in hexanes)under an atmosphere of N₂, and the mixture was stirred for 30 minutes.To this reaction mixture was added dropwise a solution of theappropriate commercially available methyl or ethyl ester or 19-26, 91 or115-121 (12.7 mmol) as a solution in THF (5 mL). After being stirred for30 minutes, the reaction mixture was allowed to warm to 0° C., andstirred for 1 h. The solvent was distilled off and the crude was dilutedwith saturated NH₄Cl (10 mL) and 10 ml of water. The mixture wasextracted with ethyl acetate (2×40 mL). The combined ethyl acetatelayers were washed with water (1×20 mL), brine (1×20 mL) and dried overanhydrous sodium sulfate. The solution was filtered and concentratedunder reduced pressure to afford the crude product. The crude waspurified by column chromatography to afford the following compounds.

# Compound Name Yield (%) 27

dimethyl (2-(2,5-dimethylfuran-3-yl)-2- oxoethyl)phosphonate 52 ¹H NMR2.23 (s, 3H), 2.53 (s, 3H), 3.31 (d, 2H, J = 22.5 Hz), 3.75 (s, 3H),3.79 (s, 3H), 6.24 (s, 1H) 28

dimethyl (2-(furan-2-yl)-2- oxoethyl)phosphonate 63 ¹H NMR 3.52 (d, 2H,J = 22.6 Hz), 3.75 (s, 3H), 3.78 (s, 3H), 6.56 (d, 1H, J = 1.6 Hz), 7.29(s, 1H), 7.62 (s, 1H) 29

dimethyl (2-(1-methyl-1H-imidazol-2- yl)-2-oxoethyl)phosphonate 45 ¹HNMR 3.80 (s, 3H), 3.83 (s, 3H), 3.88 (d, 2H, J = 22.2 Hz), 4.01 (s, 3H),7.07 (s, 1H), 7.18 (s, 1H) 30

dimethyl (2-oxo-2-(thiazol-4- yl)ethyl)phosphonate 91 ¹H NMR 3.76 (s,3H), 3.79 (s, 3H), 3.90 (d, 2H, J = 22.8 Hz), 8.32 (s, 1H), 8.85 (s, 1H)31

dimethyl2-(4,4-difluorocyclohexyl)-2- oxoethylphosphonate 82 ¹H NMR1.72-1.81 (m, 4H), 1.96-1.98 (m, 2H), 2.11-2.13 (m, 2H), 2.68-2.70 (m,1H), 3.14 (d, 2H, J = 22.4 Hz), 3.79 (d, 6H, J = 11.2 Hz) 32

dimethyl 2-(4-methylenecyclohexyl)-2- oxoethylphosphonate 67 ¹H NMR1.43-1.53 (m, 2H), 1.95-2.13 (m, 4H), 2.37-2.41 (m, 2H), 2.72-2.78 (m,1H), 3.18 (d, 2H, J = 22.5 Hz), 3.82 (d, 6H, J = 11.3 Hz), 4.68 (s, 2H)33

dimethyl 2-oxo-2-(1,4- dioxaspiro[4.5]decan-8- yl)ethylphosphonate 72 ¹HNMR 1.31-1.39 (m, 2H), 1.70-1 85 (m, 5H), 1.85-1.98 (m, 2H), 3.15 (d,2H, J = 11.2 Hz), 3.77 (d, J = 18 Hz, 6H), 3.92 (m, 4H) 34

dimethyl 2-(4-methylcyclohexyl)-2- oxoethylphosphonate 60 ¹H NMR0.88-0.90 (m, 3H), 1.20-1.50 (m, 2H), 1.50-1.65 (m, 5H), 1.80-1.95 (m,2H), 2.62-2.71 (m, 2H), 3.13 (d, J = 22.8 Hz, 2H), 3.73 and 3.80 (two s,6H) 35

dimethyl 2-(4- (iodomethylene)cyclohexyl)-2- oxoethylphosphonate 47 ¹HNMR 1.20-1.52 (m, 2H), 1.93-2.10 (m, 4H), 2.30-2.36 (m, 1H), 2.49-2.58(m, 4H), 3.07-3.10 (m, 2H), 3.73-3.76 (m, 6H), 4.60 (s, 1H) 36

dimethyl (2-oxo-2-(4-(propan-2- ylidene)cyclohexyl)ethyl)phosphonate 70¹H NMR 1.28-1.42 (m, 2H), 1.63 (s, 6H), 1.72-1.96 (m, 4H), 2.65-2.75 (m,3H), 3.12 (d, 1H, J = 21.0 Hz), 3.75 (d, 6H, J = 12.0 Hz) 37

dimethyl (2-(4- (cyclopropylmethylene)cyclohexyl)-2-oxoethyl)phosphonate 68 ¹H NMR 0.24 (s, 2H), 0.67 (d, 2H, J = 7.8 Hz),1.39-1.43 (m, 3H), 1.86-2.07 (m, 4H), 2.17-2.21 (m, 1H), 2.71-2.79 (m,2H), 3.13 (d, 2H, J = 22.5 Hz), 3.77 (d, 6H, J = 11.2 Hz), 4.50 (d, 1H,J = 9.3 Hz) 38

dimethyl (2-oxo-2-(1-pivaloylpiperidin- 4-yl)ethyl)phosphonate 68 ¹H NMR1.23 (s, 9H), 1.51 (m, 1H, 1.87 (m, 3H), 2.85 (m, 3H), 3.02 (s, 1H),3.14 (s, 1H), 3.75 (d, 6H, J = 11.2 Hz), 4.34 (m, 1H), 4.37 (m, 1H) 39

dimethyl (2-(1-methyl-1H-imidazol-5- yl)-2-oxoethyl)phosphonate 36 ¹HNMR 3.35 (d, 2H, J = 22.8 Hz), 3.74 (d, 6H, J = 11.2 Hz), 3.86 (s, 3H),7.54 (s, 1H), 7.78 (s, 1H) 40

dimethyl (2-(1-methyl-1H-imidazol-4- yl)-2-oxoethyl)phosphonate 29 ¹HNMR 3.66-3.74 (s, 3H merged with d, 2H, J = 22.5 Hz), 3.78 (d, 6H, J =11.2 Hz), 7.44 (s, 1H), 7.63 (s, 1H) 41

dimethyl (2-oxo-2-(thiazol-5- yl)ethyl)phosphonate 18 ¹H NMR 3.53 (s,1H), 3.61 (s, 1H), 3.73 (d, 6H, J = 11.2 Hz), 8.52 (s, 1H), 9.04 (s, 1H)42

dimethyl (2-(1-acetylpiperidin-4-yl)-2- oxoethyl)phosphonate 64 ¹H NMR1.44-1.69 (m, 2H), 1.83-1 89 (m, 2H), 2.07 (s, 3H), 2.66-2.73 (m, 1H),2.79-2.85 (m, 1H), 3.03-3.22 (m, 3H), 3.72-3.83 (m, 1H overlapping withd, 6H, J = 11.2 Hz), 4.53 (d, 1H, J = 13.4 Hz) 43

dimethyl (2-oxo-2-(1-(thiophene-2- carbonyl)piperidin-4-yl)ethyl)phosphonate 59 ¹H NMR 1.63 (m, 2H), 1.95 (m, 2H), 2.89 (s, 1H),3.07 (m, 2H), 3.10 (s, 1H), 3.18 (s, 1H), 3.77 (d, 6H, J = 11.2 Hz),4.38 (m, 2H), 7.02 (dd, 1H, J = 5.0 Hz, 3.7 Hz), 7.25 (dd, 1H, J = 3.7Hz, 1.1 Hz), 7.42 (dd, 1H, J = 5.1 Hz, 1.2 Hz) 44

dimethyl 2-oxo-2-(1-(2- phenylacetyl)piperidin-4- yl)ethylphosphonate 39¹H NMR 1.20-1.90 (m, 4H), 1.67 (d, 1H, J = 10.2 Hz), 1.84 (d, 1H, J =9.6 Hz), 2.55-2.75 (m, 2H), 2.90-3.15 (m, 2H), 3.65 (s, 2H), 3.70 (d,6H, J = 11.2 Hz), 3.90 (d, 1H, J = 10.2 Hz), 4.48 (d, 1H, J = 9.9 Hz),7.10-7.30 (m, 5H) 45

dimethyl 3-cyclohexyl-2- oxopropylphosphonate 70 ¹H NMR 0.60-1.15 (m,5H), 1.35-1.71 (m, 5H), 2.28 (d, 2H, J = 8.8 Hz), 2.83 (s, 1H), 2.91 (s,1H), 3.55 (s, 3H), 3.59 (s, 1H) 46

dimethyl (2-oxo-2-(4- (trityloxy)cyclohexyl)ethyl)phosphonate 79 ¹H NMR(mixture of cis and trans isomers) 1.08-1.36 (m, 5H), 1.59-1.91 (m, 3H),2.41- 2.52 (m, 1H), 3.03 and 3.13 (two d, 2H, J = 20.0 Hz), 3.35-3.79(m, 1H), 3.73-3.79 (m, 6H), 7.22-7.29 (m, 9H), 7.49-7.51 (m, 6H) 122

(trans)-methyl 4-(2- (dimethoxyphosphoryl)acetyl)cyclo-hexanecarboxylate 70 ¹H NMR 1.31-1.53 (m, 4H), 2.00-2 20 (m, 4H),2.23-2.31 (m, 1H), 2.53-2.61 (m, 1H), 3.13 (d, 2H, J = 22.6 Hz), 3.67(s, 3H), 3.79 (d, 6H, J = 11.2 Hz) 124

dimethyl (2-oxo-2-(4-(propan-2- ylidene)cyclohexyl)ethyl)phosphonate 70¹H NMR 1.28-1.42 (m, 2H), 1.63 (s, 6H), 1.72-1.96 (m, 4H), 2.65-2.75 (m,3H), 3.12 (d, 1H, J = 21.0 Hz), 3.75 (d, 6H, J = 12.0 Hz) 125

dimethyl (2-oxo-2-(spiro[2.5]octan-6- yl)ethyl)phosphonate 77 ¹H NMR0.13-0.27 (m, 4H), 0.91-0 95 (m, 2H), 1.40-2.06 (m, 6H), 2.52-2.58 (m,1H), 3.11 (d, 2H, J = 24.0 Hz), 3.75 (d, 6H, J = 12.0 Hz) 126

dimethyl (2-((trans)-4-((tert- butyldimethylsilyl)oxy)cyclohexyl)-2-oxoethyl)phosphonate 96 ¹H NMR 0.11 (s, 6H), 0.82 (s, 9H), 1.19-1.32 (m,4H), 1.85-1.88 (m, 4H), 2.41-2.47 (m, 1H), 3.08 (d, 2H, J = 24.0 Hz),3.72 (s, 3H), 3.74 (s, 3H) 127

dimethyl (2-((trans)-4- (benzyloxy)cyclohexyl)-2- oxoethyl)phosphonate16 ¹H NMR 1.13-1.41 (m, 4H), 1.93-2 02 (m, 2H), 2.12-2.15 (m, 2H),2.51-2.56 (m, 1H), 3.11 (d, 2H, J = 24 Hz), 3.27-3.32 (m, 1H), 3.75 (d,6H, J = 12 Hz ), 7.22-7.32 (m, 5H) 128

dimethyl (2-(cis-4- benzamidocyclohexyl)-2- oxoethyl)phosphonate 83 ¹HNMR 1.76-1.85 (m, 8H), 2.78-2 79 (m, 1H), 3.18 (d, 2H, J = 22.8 Hz),3.82 (d, 6H, J = 11.2 Hz), 4.21-4.25 (m, 1H), 7.40-7.52 (m, 3H),7.76-7.78 (m, 2H) 129

dimethyl (2-(trans-4- benzamidocyclohexyl)-2- oxoethyl)phosphonate 54 ¹HNMR 1.29 (dq, 2H, J = 3.1, 12.1 Hz), 1.54 (dq, 2H, J = 3.0, 11.5 Hz),2.04 (d, 2H, J = 12.9 Hz), 2.12 (dd, 2H, J = 3.0, 12.6 Hz), 2.60 (tt,1H, J = 3.4, 12.0 Hz), 3.15 (d, 2H, J = 22.6 Hz), 3.79 (d, 6H, J = 11.2Hz), 3.93-3.99 (m, 1H), 5.98 (d, 1H, J = 7.7 Hz), 7.41-7.45 (m, 2H),7.48-7.52 (m, 2H), 7.74 (d, 2H, J = 7.1 Hz) 130

dimethyl (2-oxo-2-(4-(2- (trityloxy)ethylidene)cyclohexyl)eth-yl)phosphonite 42 ¹H NMR 1.26-1.60 (m, 2H), 1.35-1 37 (m, 1H), 1.80-2.30(m, 3H), 2.25-2.40 (m, 2H), 2.70-2.76 (m, 1H), 3.05 (d, J = 27 Hz, 2H),3.57-3.61 (m, 2H), 3.71-3.75 (d, J = 12 Hz, 2H), 7.19-7.32 (m, 9H),7.44-7.51 (m, 6H) 131

tert-butyl 3-(2- (dimethoxyphosphoryl)acetyl)azetidine- 1-carboxylate 99¹H NMR 1.43 (s, 9H), 3.11 (d, J = 24 Hz, 2H), 3.68-3.82 (m, 7H),3.81-4.12 (m, 4H) 132

dimethyl (2-oxo-2-(pyridin-2- yl)ethyl)phosphonate 56 ¹H NMR 3.69-3.77(m, 6H), 3.96-4 04 (m, 2H), 7.45-7.48 (m, 1H), 7.80-7.85 (m, 1H),8.03-8.09 (m, 1H), 8.66-8.69 (m, 1H) 133

dimethyl (2-oxo-2-(pyridin-3- yl)ethyl)phosphonate 65 ¹H NMR 3.60-3.80(m, 8H), 7, 41-7 45 (m, 1H), 8.26-8.29 (m, 1H), 8.78-8.79 (m, 1H), 9.18(m, 1H) 134

dimethyl (2-oxo-2-(4- (trifluoromethyl)cyclohexyl)ethyl)phos- phonate 30¹H NMR 1.55-1.64 (m, 4H), 1.75-1 77 (m, 2H), 204-2.16 (m, 3H), 2.83-2.84(m, 1H), 3.14 (d, J = 22.4 Hz, 2H), 3.78 (d, J = 11.2 Hz, 6H) 135

dimethyl (2-((1s,4s)-4- (benzyloxy)cyclohexyl)-2- oxoethyl)phosphate 17¹H NMR 1.47-1.55 (m, 2H), 1.66-1.71 (m, 2H), 1.78-1.85 (m, 2H),1.95-1.99 (m, 2H), 2.58-2.62 (m, 1H), 3.14 (d, 2H, J = 22.4 Hz),3.60-3.63 (m, 1H), 3.78 (d, 6H, J = 11.2 Hz), 4.48 (s, 2H), 7.24-7.33(m, 5H)

Example 23 General Procedure for the Synthesis of2-(5H-imidazo[5,1-a]isoindol-5-yl)ethanones by Horner-Wadsworth-EmmonsReaction Followed by Cyclization

To a suspension of 95% NaH (17.4 mg, 0.7 mmol) in THF (3 mL) at 0° C.was added the appropriate phosphonate reagent 27-46, 89, 90 or 122-135(0.75 mmol) as a solution in THF (2 mL) and the mixture was stirred for40 min. The appropriate 2-(1-trityl-1H-imidazol-4-yl)benzaldehyde wasadded as a solution in THF (3 mL) drop wise over a period of 3 min. Thereaction was allowed to warm to RT and stirred overnight. The solventwas removed under reduced pressure and the crude was diluted withsaturated NH₄Cl (10 mL) and water (10 mL). The aqueous layer wasextracted with CH₂Cl₂ (2×20 mL) and the combined organic fractions werewashed with brine (15 mL), dried over Na₂SO₄ and concentrated underreduced pressure to afford the crude product. To the crude residue wasadded AcOH (1 mL) and MeOH (3 mL) and the solution was stirred at 90° C.for 2 h. After cooling to rt, the solvent was distilled off and thecrude was stirred in a mixture of sat'd K₂CO₃ (5 mL) and EtOAc (5 mL).The organic layer was separated and the aqueous layer was extracted withEtOAc (2×10 mL). The combined organic layers were washed with water,brine and dried (Na₂SO₄) and the solvent evaporated under reducedpressure. The crude residue was purified by flash column chromatographyon silica gel to afford the following compounds.

Yield # Compound Name (%) 47

1-(cyclohex-1-en-1-yl)-2-(5H- imidazo[5,1-a]isoindol-5-yl)ethanone 54 ¹HNMR 1.64-1.68 (m, 4H), 2.23-2.33 (m, 4H), 3.12 (dd, 1H, J = 9.8, 17.8Hz), 3.36 (dd, 1H, J = 3.2, 18.0 Hz), 5.72 (dd, 1H, J = 3.6, 7.6 Hz),6.86-6.88 (m, 1H), 7.17 (s, 1H), 7.32 (d, 1H, J = 7.6 Hz), 7.38 (t, 1H,J = 7.4 Hz), 7.55 (d, 1H, J = 7.2 Hz), 7.65 (s 1H) 48

1-(2,5-dimethylfuran-3-yl)-2-(6- fluoro-5H-imidazo[5,1-a]isoindol-5-yl)ethanone 93 ¹H NMR 2.22 (s, 3H), 2.60 (s, 3H), 2.97 (dd, 1H, J =10.8, 18.4 Hz), 3.72 (d, 1H, J = 18.2Hz), 5.86 (d, 1H, J = 10.7 Hz),6.11 (s, 1H), 6.93 (t, 1H, J = 8.5 Hz), 7.16 (s, 1H), 7.30-7.37 (m, 2H).7.74 (s, 1H) 49

2-(6-fluoro-5H-imidazo[5,1- a]isoindol-5-yl)-1-(furan-2- yl)ethanone 65¹H NMR 3.16 (dd, 1H, J = 10.5, 18.4 Hz), 3.85 (d, 1H, J = 18.4 Hz), 5.86(d, 1H, J = 10.5 Hz), 6.54 (s, 1H), 6.92 (t, 1H, J = 8.9 Hz), 7.14 (s,1H), 7.24-7.35 (m, 3H), 7.57 (s, 1H), 7.74 (s, 1H) 50

2-(6-fluoro-5H-imidazo[5,1- a]isoindol-5-yl)-1-(1-methyl-1H-imidazol-2-yl)ethanone 39 ¹H NMR 3.56 (dd, 1H, J = 12.0, 20.0 Hz), 4.07(s, 3H), 4.13 (d, 1H, J = 20.0 Hz), 5.86 (d, 1H, J = 12.0 Hz), 6.92 (t,1H, J = 8.0 Hz), 7.09 (d, 1H, J = 8.0 Hz), 7.15 (s, 1H), 7.31-7.34 (m,3H), 7.71 (s, 1H) 51

2-(5H-imidazo[5,1-a]isoindol-5-yl)-1- (thiazol-4-yl)ethanone 58 ¹H NMR3.62 (dd, 1H, J = 9.7, 18.8 Hz), 3.92 (dd, 1H, J = 3.0, 18.9 Hz), 5.79(d, 1H, 9.5 Hz), 7.18 (s, 1H), 7.26-7.28 (m, 1H overlap with CHCl3),7.36-7.40 (m, 2H), 7.55 (d, 1H, J = 7.4 Hz), 7.75 (s, 1H), 8.38 (s, 1H),8.82 (s, 1H) 52

1-(4,4-difluorocyclohexyl)-2-(6- fluoro-5H-imidazo[5,1-a]isoindol-5-yl)ethanone 81 ¹H NMR 1.65-1.82 (m, 4H), 1.90-2.01 (m, 2H), 2.11-2.16(m, 2H), 2.44-2.48 (m, 1H), 2.79 (dd, 1H, J = 10.4 Hz, 18.4 Hz), 3.52(dd, 1H, J = 2 Hz, 18.4 Hz), 5.72 (d, 1H, J = 10.4 Hz), 6.92 (t, 1H, J =8.8 Hz), 7.15 (s, 1H), 7.28-7.35 (m, 2H), 7.58 (s, 1H) 53

1-(4,4-difluorocyclohexyl)-2-(5H- imidazo[5,1-a]isoindol-5-yl)ethanone96 ¹H NMR 1.73-1.80 (m, 4H), 1.91-1.95 (m, 2H), 2.10-2.14 (m, 2H),2.41-2.47 (m, 1H), 2.90 (dd, 1H, J = 9.4 Hz, 18.8 Hz), 3.21 (dd, 1H, J =3.6 Hz, 18.4 Hz), 5.60 (dd, 1H, J = 3.4 Hz, 9.4 Hz), 7.13 (s, 1H),7.22-7.28 (m, 2H), 7.36 (t, 1H, J = 7.2 Hz), 7.51 (d, 1H, J = 7.6 Hz),7.57 (s, 1H) 54

2-(5H-imidazo[5,1-a]isoindol-5-yl)-1- (4-methylenecyclohexyl)ethanone ¹HNMR 1.30-1.50 (m, 2H), 1.80-2.05 (m, 3H), 2.20-2.32 (m, 2H), 2.40-2.50(m, 1H), 2.58-2.67 (m, 1H), 2.78-2.88 (m, 1H), 3.16-3.17 (m, 1H),5.50-5.54 (m, 1H), 7.13-7.17 (m, 1H), 7.20-7.30 (m, 2H), 7.43-7.45 (m,1H), 7.52 (s, 1H) 55

2-(6-fluoro-5H-imidazo[5,1- a]isoindol-5-yl)-1-(4-methylenecyclohexyl)ethanone 64 ¹H NMR 1.30-1.60 (m, 2H), 1.90-2.10 (m,3H), 2.32-2.35 (m, 2H), 2.50-2.60 (m, 1H), 2.60-2.72 (m, 1H), 2.76-2.84(m, 1H), 3.52 (d, J = 18.4 Hz, 1H), 4.63 (s, 2H), 5.73 (d, J = 10.4 Hz,1H), 6.91-6.96 (m, 1H), 7.20-7.30 (m, 2H), 7.43-7.45 (m, 1H), 7.52 (s,1H) 56

2-(6-fluoro-5H-imidazo[5,1- a]isoindol-5-yl)-1-(1,4-dioxaspiro[4.5]decan-8-yl)ethanone 84 ¹H NMR (CD₃OD) 1.48-1.91 (m, 6H),2.35-2.65 (m, 2H), 3.58-3.65 (m, 1H), 3.91 (s, 4H), 5.79-5.82 (m, 1H),7.01-7.07 (m, 1H), 7.16 (m, 1H), 7.42-7.45 (m, 2H), 7.70 (s, 1H) 57

2-(6-fluoro-5H-imidazo[5,1- a]isoindol-5-yl)-1-(4-methylcyclohexyl)ethanone 87 ¹H NMR 0.80-0.95 (m, 3H), 1.24-1.40 (m,2H), 1.40-1.68 (m, 5H), 1.70-2.00 (m, 2H), 2.40-2.55 (m, 1H), 2.72-2.84(m, 1H), 3.48 (d, J = 18.4 Hz, 1H), 5.75 (d, J = 10.4 Hz, 1H), 6.89-6.95(m, 1H), 7.15 (s, 1H), 7.26-7.38 (m, 2H), 7.62 (s, 1H) 58

2-(6-fluoro-5H-imidazo[5,1- a]isoindol-5-yl)-1-(4-(iodomethylene)cyclohexyl)ethanone 46 ¹H NMR (CD₃OD) 1.20-1.52 (m, 2H),1.80-2.20 (m, 4H), 2.30-2.36 (m, 1H), 2.45-2.80 (m, 3H), 2.90-3.02 (m,1H), 3.59-3.64 (m, 1H), 4.63 (s, 1H), 5.75-5.80 (m, 1H), 7.02- 7.08 (m,1H), 7.15 (s, 1H), 7.42-7.47 (m, 2H), 7.65 (s, 1H). 59

2-(9-fluoro-5H-imidazo[5,1- a]isoindol-5-yl)-1-(4-methylcyclohexyl)ethanone 55 ¹H NMR (CD₃OD) 0.80-0.95 (m, 3H), 1.24-1.40(m, 2H), 1.40-1.68 (m, 5H), 1.70-2.00 (m, 2H), 2.40-2.55 (m, 1H),2.72-2.84 (m, 1H), 3.48 (d, J = 18.4 Hz, 1H), 5.49-5.59 (m, 1H),7.10-7.18 (m, 2H), 7.60-8.00 (m, 1H) 60

2-(6-fluoro-5H-imidazo[5,1- a]isoindol-5-yl)-1-(4-(propan-2-ylidene)cyclohexyl)ethanone 36 ¹H NMR 1.30-1.52 (m, 2H), 1.64 (s, 6H),1.70-1.81 (m, 2H), 1.85-1.98 (m, 2H), 2.52- 2.62 (m, 1H), 2.68-2.74 (m,2H), 2.80 (dd, 1H, J = 18.5 Hz, 10.6 Hz), 3.50 (dd, 1H, J = 18.5 Hz, 2.2Hz), 5.75 (d, 1H, J = 9.27 Hz), 6.90-6.96 (m, 1H), 7.17 (s, 1H),7.32-7.36 (m, 2H), 7.59 (s, 1H) 61

1-(4- (cyclopropylmethylene)cyclohexyl)- 2-(6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)ethanone 49 ¹H NMR 0.24 (s, 2H), 0.67 (d, 2H, J = 7.8Hz), 1.43-1.49 (m, 3H), 1.82-2.15 (m, 3H), 2.12-2.28 (m, 1H), 2.50-2.62(m, 1H), 2.75-2.85 (m, 2H), 3.52 (d, 1H, J = 18.6 Hz), 4.52 (d, 1H, J =9.3 Hz), 5.75 (d, 1H J = 10.2 Hz), 6.89-6.95 (m, 1H), 7.16 (s, 1H),7.25-7.36 (m, 3H), 7.59 (s, 1H) 62

1-(4-(2-(5H-imidazo[5,1-a]isoindol- 5-yl)acetyl)piperidin-1-yl)-2, 2-dimethylpropan-1-one 42 ¹H NMR 1.26 (s, 9H), 1.60 (m, 2H), 1.88 (m, 2H),2.61 (m, 1H), 2.84 (m, 2H), 2.89 (dd, 1H, J = 9.39 Hz, 18.6 Hz), 3.22(dd, 1H, J = 3.6 Hz, 18.3 Hz), 4.41 (m, 2H), 5.62 (dd, 1H, J = 3.54 Hz,9.45 Hz), 7.16 (s, 1H), 7.24 (m, 2H), 7.37 (m, 1H), 7.53 (d, 1H, J =7.56 Hz), 7.59 (s, 1H) 63

2-(6-fluoro-5H-imidazo[5,1- a]isoindol-5-yl)-1-(1-methyl-1H-imidazol-5-yl)ethanone 62 ¹H NMR 3.13-3.20 (m, 1H), 3.85-3.89 (m, 1H),4.0 (s, 3H), 5.79 and 5.89 (two d, 1H, J = 10.4 Hz), 6.96 (t, 1H, J =8.8 Hz), 7.20 (s, 1H), 7.33-7.38 (m, 2H), 7.62 (s, 1H), 7.74 and 7.81(two s, 3H) 64

2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(1-methyl-1H-imidazol-4-yl)ethanone 24 ¹H NMR 3.42 (d, 1H, J = 9.9 Hz),3.48 (d, 1H, J = 8.7 Hz), 3.75 (s, 3H), 5.75 (dd, 1H, J = 3.4 Hz, 9.8Hz), 7.26-7.19 (m, 1H), 7.14 (s, 1H), 7.35 (m, 2H), 7.41 (d, 1H, J = 1.0Hz), 7.52 (dd, 1H, J = 1.2 Hz, 7.35 Hz), 7.71 (s, 1H), 7.67 (d, 1H, J =1.2 Hz), 65

2-(5H-imidazo[5,1-a]isoindol-5-yl)-1- (thiazol-5-yl)ethanone 30 ¹H NMR3.40 (dd, 1H, J = 9.6 Hz, 18.4 Hz), 3.71 (dd, 1H, J = 3.2 Hz, 18.0 Hz),5.80 (dd, 1H, J = 2.8 Hz, 9.2 Hz), 7.21 (s, 1H), 7.29 (d, 1H, J = 7.2Hz), 7.36-7.41 (m, 2H), 7.57 (d, 1H, J = 8.0 Hz), 8.41 (s, 1H), 7.73 (s,1H), 9.0 (s, 1H), 66

1-(1-acetylpiperidin-4-yl)-2-(5H- imidazo[5,1-a]isoindol-5-yl)ethanone74 ¹H NMR 1.57 (m, 2H), 1.90 (m, 2H), 2.09 (s, 3H), 2.60 (m, 2H), 2.91(m, 1H), 3.07-3.26 (m, 2H), 3.82 (m, 1H), 4.58 (m, 1H), 5.62 (m, 1H),7.16 (s, 1H) 7.29 (m, 2H), 7.37 (m, 1H), 7.53 (d, 1H, J = 10.4 Hz), 7.58(d, 1H, J = 4.8 Hz) 67

2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(1-thiophene-2-carbonyl)piperidin-4- yl)ethanone ¹H NMR a 68

1-(4-(2-(5H-imidazo[5,1-a]isoindol- 5-yl)acetyl)piperidin-1-yl)-2-phenylethanone 49 ¹H NMR 1.20-1.90 (m, 4H), 2.40-3.33 (m, 5H), 3.73 (s,2H), 3.89 (d, 1H, J = 13.5 Hz), 4.59 (d, 1H, J = 13.5 Hz), 5.50-5.70 (m,1H), 7.15-7.45 (m, 9H), 7.53 (d, 1H, J = 7.5 Hz), 7.68 (d, 1H, J = 7.8Hz) 69

1-cyclohexyl-3-(5H-imidazo[5,1- a]isoindol-5-yl)propan-2-one 82 ¹H NMR0.85-1.35 (m, 5H), 1.55-1.175 (m, 5H), 1.80-1.95 (m, 1H), 2.25-2.38 (m,2H), 2.70-2.80 (m, 1H), 3.16 (dd, 1H, J = 2.4, 14.8 Hz), 5.50-5.60 (m,1H), 7.16 (s, 1H), 7.20-7.30 (m, 3H), 7.35 (t, 1H, J = 5.4 Hz), 7.41 (d,1H, J = 5.4 Hz), 7.73 (s, 1H) 70

1-cyclohexyl-3-(6-fluoro-5H- imidazo[5,1-a]isoindol-5-yl)propan- 2-one78 ¹H NMR 0.80-1.40 (m, 5H), 1.45-2.00 (m, 6H), 2.32 (t, 2H, J = 9.3Hz), 2.80-2.60 (m, 1H), 3.46 (d, 1H, J = 18.6 Hz), 5.72 (d, 1H, J = 10.5Hz), 6.92 (t, 1H, J = 9.3 Hz), 7.18 (s, 1H), 7.25-7.40 (m, 2H), 7.71 (s,1H) 71

2-(6-fluoro-5H-imidazo[5,1- a]isoindol-5-yl)-1-(4-hydroxycyclohexyl)ethanone 89 ¹H NMR (mixture of cis and trans isomers)1.25-1.77 (m, 6H), 1.90-2.06 (m, 3H), 2.34- 2.42 (m, 1H), 2.80 (dd, 1H,J = 10.8 Hz, 18.8 Hz), 3.51 (d, 1H, J = 18.8 Hz), 3.60-3.62 and3.97-4.01 (m, 1H), 5.73-5.76 (m, 1H), 6.93 (t, 1H, J = 8.4 Hz), 7.17 (s,1H), 7.30- 7.37 (m, 2H), 7.59 and 7.62 (two s, 1H) 72

1-cyclohexyl-2-(5H-imidazo[5,1- a]isoindol-5-yl)ethanone 86 ¹H NMR 1.25(m, 5H), 1.79 (m, 5H), 2.38 (m, 1H), 2.89 (dd, 1H, J = 18.0 Hz, 9.0 Hz),3.18 (dd, 1H, J = 18 Hz, 3.0 Hz), 5.63 (m, 1H), 7.16 (s, 1H), 7.21-7.28(m, 2H), 7.37 (t, 1H, J = 7.5 Hz), 7.53 (d, 1H, J = 6 Hz), 7.60 (s, 1H)aThe compound was not characterized and was used as such for the nextsynthetic step 136

1-cyclohexyl-2-(5H-imidazo[5,1- a]isoindol-5-ylidene)ethanone 62 ¹H NMRIndistinguishable mixture of E/Z isomers 1.26-1.48 (m, 8.9H), 1.63-1.94(m, 13.7H), 2.58-2.62 (m, 0.6H), 3.33-3.38 (m, 1H), 6.40 (s, 0.4H), 6.60(s, 0.53H), 7.15 (d, 0.8 Hz, J = 6.0 Hz), 7.25-7.28 (m merged withCHCl3, 0.8H), 7.43-7.49 (m, 3H), 7.63- 7.67 (m, 2H), 7.74-7.77 (m, 3H),7.93 (s, 1H), 8.06 (d, 1H, J = 8.0 Hz), 9.25 (s, 0.4H), 9.43 (s, 0.8 H)137

(trans)-methy 4-(2-(5H-imidazo[5,1- a]isoindol-5-yl)acetyl)cyclohexanecarboxylate 90 ¹H NMR 1.38-1.49 (m, 4H), 1.95-2.11(m, 4H), 2.27-2.32 (m, 1H), 2.27-2.42 (m, 1H), 2.91 (dd, J = 9.5, 18.5Hz, 1H), 3.21 (dd, J = 3.5, 18.5 Hz, 1H), 3.67 (s, 3H), 5.63 (dd, J =3.3, 9.5 Hz), 7.17 (s, 1H), 7.22-7.29 (m, 2H), 7.38 (t, 1H, J = 7.5 Hz),7.54 (d, 1H, J = 7.6 Hz), 7.60 (s, 1H) 139

2-(6-fluoro-5H-imidazo[5,1- a]isoindol-5-yl)-1-(4-(propan-2-ylidene)cyclohexyl)ethanone 36 ¹H NMR 1.30-1.52 (m, 2H), 1.64 (s, 6H),1.70-1.81 (m, 2H), 1.85-1.98 (m, 2H), 2.52- 2.62 (m, 1H), 2.68-2.74 (m,2H), 2.80 (dd, 1H, J = 18.5 Hz, 10.6), 3.50 (dd, 1H, J = 18.5 Hz, 2.2Hz), 5.75 (d, 1H, J = 9.27 Hz), 6.90-6.96 (m, 1H), 7.17 (s, 1H),7.32-7.36 (m, 2H), 7.59 (s, 1H) 140

2-(5H-imidazo[5,1-a]isoindol-5-yl)- 1-(spiro[2.5]octan-6-yl)ethanone 59¹H NMR 0.18-0.30 (m, 4H), 0.90-0.98 (m, 2H), 1.52-1.87 (m, 6H),2.38-2.53 (m, 1H), 2.91 (dd, 1H, J = 18.4, 9.60 Hz), 3.20 (dd, 1H, J =18.47, 3.6 Hz), 5.58-5.65 (m, 1H), 7.15 (s, 1H), 7.21-7.27 (m, 2H), 7.36(t, 1H, J = 7.60 Hz), 7.52 (d, 1H, J = 7.60 Hz), 7.61 (s, 1H) 141

1-((trans)-4-((tert- butyldimethylsilyl)oxy)cyclohexyl)-2-(6-fluoro-5H-imidazo[5,1- a]isoindol-5-yl)ethanone 79 ¹H NMR 0.028 (s,6H), 0.88 (s, 9H), 11.27-1.96 (m, 8H), 2.32-2.38 (m, 1H), 2.80 (dd, 1H,J = 18.8, 10.6 Hz), 3.48-3.57 (m, 2H), 5.75 (d, J = 9.3 Hz), 6.91-6.95(m, 1H), 7.17 (s, 1H), 7.23-7.39 (m, 2H), 7.59 and 7.64 (two s, 1H) 142

1-((trans)-4-(benzyloxy)cyclohexyl)- 2-(6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)ethanone 72 ¹H NMR 1.15-1.54 (m, 4H), 1.91-2.20 (m, 4H),2.37-2.43 (m, 1H), 2.80 (dd, 1H, J = 18.5, 10.5 Hz), 3.31-3.36 (m, 1H),3.51 (d, 1H, J = 18.6 Hz), 4.55 (s, 2H), 5.74 (d, 1H, J = 10.3 Hz), 6.93(t, 1H, J = 8.0 Hz), 7.17 (s, 1H), 7.29-7.39 (m, 7H), 7.59 and 7.78 (twos, 1H) 143

1-((trans)-4-(benzyloxy)cyclohexyl)- 2-(5H-imidazo[5,1-a]isoindol-5-yl)ethanone 81 ¹H NMR 1.14-1.50 (m, 4H), 1.92-2.01 (m, 2H), 2.15-2.19(m, 2H), 2.34-2.43 (m, 1H), 2.90 (dd, 1H, J = 18, 9 Hz), 3.19 (dd, 1H, J= 24, 6 Hz), 3.30-3.37 (m, 1H), 4.49 and 4.55 (two s, 2H), 5.61 (dd, 1H,J = 10.5, 4.5 Hz), 7.16-7.39 (m, 9H), 7.53 (d, 1H, J = 9 Hz), 7.62 (s,1H) 144

N-((cis)-4-(2-(5H-imidazo[5,1- a]isoindol-5-yl)acetyl)cyclohexyl)benzamide 53 ¹H NMR 1.25-1.34 (m, 2H), 1.53-1.63(m, 2H), 1.98-2.08 (m, 2H), 2.20 (t, 2H, J = 11.6 Hz), 2.36 (t, 1H, J =12.2 Hz), 2.90 (dd, 1H, J = 9.4, 18.6 Hz), 3.25 (dd, 1H, J = 3.2, 18.4Hz), 3.93-4.00 (m, 1H), 5.63 (dd, 1H, J = 3.2, 9.2 Hz), 6.32 (d, 1H, J =6.8 Hz), 7.19 (s, 1H), 7.26-7.35 (m, 2H, merged with chloroform),7.38-7.43 (m, 3H), 7.48 (d, 1H, J = 7.2 Hz), 7.55 (d, 1H, J = 7.6 Hz),7.71 (s, 1H), 7.76 (d, 2H, J = 7.6 Hz) 145

N-((trans)-4-(2-(5H-imidazo[5,1- a]isoindol-5-yl)acetyl)cyclohexyl)benzamide 69 ¹H NMR 1.19-1.36 (m, 2H), 1.48-1.65(m, 2H), 1.93-2.07 (m, 2H), 2.18-2.23 (m, 2H), 2.35 (tt, 1H, J = 3.2,12.2 Hz), 2.90 (dd, 1H, J = 9.5, 18.4 Hz), 3.22 (dd, 1H, J = 3.6, 18.4Hz), 3.92-3.99 (m, 1H), 5.62 (dd, 1H, J = 3.4, 9.4 Hz), 6.23 (d, 1H, J =7.6 Hz), 7.23- 7.32 (m, 3H, merged with chloroform), 7.34-7.42 (m, 3H),7.46-7.50 (m, 1H), 7.54 (d, 1H, J = 7.6 Hz), 7.63 (s, 1H), 7.76 (d, 2H,J = 7.6 Hz) 146

1-(4-(2- hydroxyethylidene)cyclohexyl)-2- (5H-imidazo[5,1-a]isoindol-5-yl)ethanone 85 ¹H NMR 1.26-1.50_(m, 2H), 1.70-2.30 (m, 4H), 2.31-2.40(m, 1H), 2.41-2.75 (m, 2H), 2.76-2.90 (m, 1H), 3.15-3.25 (m, 1H),4.08-4.13 (m, 1H), 5.25-5.40 (m, 1H), 5.51-5.60 (m, 1H), 7.12 (s, 1H),7.13-7.40 (m, 2H), 7.48-7.60 (m, 3H) 147

tert-butyl 3-(2-(5H-imidazo[5,1- a]isoindol-5-yl)acetyl)azetidine-1-carboxylate 77 ¹H NMR 1.38 (s, 9H), 2.85-2.92 (m, 1H), 3.20-3.25 (m,1H), 3.44-3.48 (m, 1H), 3.65- 3.70 (m, 2H), 4.01-4.28 (m, 2H), 5.63-5.66(m, 1H), 7.16 (s, 1H), 7.21-7.31 (m, 2H), 7.36-7.40 (m, 1H), 7.53-7.55(m, 1H), 7.66 (s, 1H) 148

2-(5H-imidazo[5,1-a]isoindol-5-yl)-1- (pyridin-2-yl)ethanone 75 ¹H NMR3.60 (dd, J = 10, 19.2Hz, 1H), 3.91 (dd, J = 3.2, 19.2Hz, 1H), 5.65 (dd,J = 3.2, 10 Hz, 1H), 7.08 (s, 1H), 7.13-7.17 (m, 1H), 7.25-7.30 (m, 2H),7.38-7.45 (m, 2H), 7.66 (s, 1H), 7.78-7.80 (m, 1H), 8.05 (d, J = 8 Hz,1H), 8.51-8.53 (m, 1H) 149

2-(5H-imidazo[5,1-a]isoindol-5-yl)-1- (pyridin-3-yl)ethanone 89 ¹H NMR3.57-3.67 (m, 1H), 3.80-3.95 (m, 1H), 6.01-6.05 (m, 1H), 7.27-7.73 (m,6H), 8.29-8.36 (m, 1H), 8.61 (s, 1H), 8.86 (d, J = 3 Hz, 1H), 9.18 (s,1H) 150

2-(5H-imidazo[5,1-a]isoindol-5-yl)-1- (pyridin-4-yl)ethanone 21 ¹H NMR3.42-3.49 (dd, J = 9.2, 18.8 Hz, 1H), 3.76 (dd, J = 3.6, 18.8Hz, 1H),5.83 (dd, J = 3.2, 9.2 Hz, 1H), 7.20 (s, 1H), 7.28-7.32 (m, 1H),7.38-7.45 (m, 2H), 7.58-7.60 (m, 1H), 7.74-7.75 (m, 2H), 7.81 (s, 1H),8.84-8.86 (m, 2H) 151

2-(5H-imidazo[5,1-a]isoindol-5-yl)-1- (4-(trifluoromethyl)cyclohexyl)ethanone 50 ¹H NMR 1.55-1.81 (m, 5H),_2.08-2.29 (m, 4H), 2.58-2.62 (m, 1H), 2.94 (dd, J = 9, 18 Hz, 1H), 3.22(dd, J = 6, 18 Hz, 1H), 5.68 (dd, J = 6, 9 Hz, 1H), 7.18-7.57 (m, 5 H),7.81 and 7.83 (two s, 1H) 152

2-(6-fluoro-5H-imidazo[5,1- a]isoindol-5-yl)-1-(4-(trifluoromethyl)cyclohexyl)ethanone 53 ¹H NMR 1.51-1.83 (m, 6H),1.95-2.21 (m, 3H), 2.58-2.62 (m, 1H), 2.79 (dd, J = 9, 18 Hz, 1H),3.46-3.55 (m, 1H), 5.73-5.79 (m, 1H), 6.89-6.98 (m, 1H), 7.20-7.38 (m,4H), 7.71 (s, 1H) 153

1-((cis)-4-(benzyloxy)cyclohexyl)-2-(6-fluoro-5H-imidazo[5,1-a]isoindol- 5-yl)ethanone 77 ¹H NMR 1.67-2.04(m, 8H), 2.39-2.45 (m, 1H), 2.79 (dd, 1H, J = 18.6, 10.6 Hz), 3.50 (dd,1H, J = 16.4, 2.4 Hz), 3.60-3.65 (m, 1H), 4.49 and 4.55 (two s, 1H),5.76 (d, 1H, J = 8.8 Hz), 6.91-6.95 (m, 1H), 7.17 (s, 1H), 7.26-7.35 (m,7H), 7.63 (s, 1H)

Example 241-(Cyclohex-3-enyl)-2-(6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)ethanone

71 (270 mg, 0.86 mmol) was dissolved in benzene (7 mL) andp-toluenesulfonic acid (444 mg, 2.58 mmol) was added. The reactionmixture was heated at 100° C. for 48 h and concentrated. The residue wasbasified with aqueous potassium carbonate solution (5 mL). The aqueoussolution was extracted with ethyl acetate (2×20 mL). The combinedorganic layers were washed with water, brine, dried over Na₂SO₄,filtered and concentrated. The residue was purified by flash columnchromatography to afford the title compound 155 as yellow gel (218 mg,86%). ¹H NMR: 1.35-1.71 (m, 1H), 1.88-2.40 (m, 5H), 2.62-2.67 (m, 1H),2.74-2.87 (m, 1H), 3.47-3.58 (m, 1H), 5.66-5.75 (m, 3H), 6.91 (t, 1H,J=8.9 Hz), 7.15 (s, 1H), 7.26-7.35 (m, 2H), 7.62 (d, 1H, J=9.8 Hz).

Example 25 General Procedure for the Reduction of2-(5H-imidazo[5,1-a]isoindol-5-yl)ethanones to2-(5H-imidazo[5,1-a]isoindol-5-yl)ethanols

To a solution of the appropriate ketone (9-18, 47-72, 136-153, 155,1256, 1287, 1300, 1306, 1326, 1328, 1334, 1348 or 1353) (0.25 mmol) inMeOH (2 mL) at 0° C., was added NaBH₄ (0.75 mmol) and the solution wasallowed to stir for 1 h. The solvent was removed under reduced pressureand 2M HCl (2 mL) was added to the crude. The solution was allowed tostir for 10 min and was made basic by satd. K₂CO₃ solution. The aqueouslayer was extracted with CH₂Cl₂ (3×5 mL). The combined organic layerswere washed with brine, dried (MgSO4) and concentrated under reducedpressure to afford the crude residue. The crude was purified by columnchromatography using 1-10% MeOH:DCM gradient to afford the followingcompounds.

Yield # Compound Name (%) 1286

2-(6-chloro-5H-imidazo[5,1- a]isoindol-5-yl)-1-cyclohexylethanol 98 ¹HNMR (a mixture of diastereomers) 0.96-1.35 (m, 6H), 1.60-1.86 (m, 5H),2.10 (m, 1H), 2.52-2.69 (m, 1H), 3.58-3.69 (m, 1H), 5.31 and 5.59 (twodd, 1H, J = 6.0 Hz, 2.80 Hz, J₂ = 10.4 Hz, 2.80 Hz), 7.16-7.19 (m, 2H),7.28 (m, 1H), 7.41 (t, 1H, J = 5.4 Hz), 7.82 and 7.94 (two s, 1H) 1304

1-cyclohexyl-2-(5H-imidazo[5,1- a]isoindol-5-yl)ethanol 79 ¹H NMR (amixture of diastereomers) 1.10-1.37 (m, 6H), 1.66-1.80 (m, 5H), 2.05 (m,2H), 2.15 (m, 1H), 3.72 (m, 1H), 5.36 and 5.46 (two m, 1H), 7.16 (s,1H), 7.25 (m, 1H), 7.34 (m, 1H), 7.43 (d, 1H, J = 7.6 Hz), 7.54 (d, 1H,J = 7.6 Hz), 7.80 (s, 1H) 1327

2-(5H-imidazo[5,1-a]isoindol-5-yl)-1- (2-nitrophenyl)ethanol 73 ¹H NMR(a mixture of diastereomers) 2.29 (m, 1H), 2.61 (m, 1H), 5.44 (m, 1H),5.71 (dd, 1H, J = 9.0 Hz, 4.5 Hz), 7.08 (s, 1H), 7.27 (m, 2H), 7.34 (m,1H), 7.45-7.53 (m, 3H), 7.68 (m, 1H), 7.95 (m, 2H) 1307

2-(5H-imidazo[5,1-a]isoindol-5-yl)-1- (3-nitrophenyl)ethanol 39 ¹H NMR(a mixture of diastereomers) 2.32-2.40 (m, 1H), 2.48-2.58 (m, 1H),5.06-5.11 (m, 1H), 5.41 and 5.61 (two m, 1H), 7.09 (s, 1H), 7.30-7.43(m, 2H), 7.48-7.57 (m, 3H), 7.64-7.72 (m, 2H), 8.12-8.19 (m, 2H) 1329

tert-butyl (2-(1-hydroxy-2-(5H- imidazo[5,1-a]isoindol-5-yl)ethyl)phenyl)carbamate 50 ¹H NMR (a mixture of diastereomers) 1.50and 1.55 (two s, 9H), 2.50 and 2.78 (two m, 2H), 5.02 and 5.07 (two m,1H), 5.19 and 5.56 (two m, 1H), 6.93-7.02 (m, 2H), 7.12 (d, 1H, J = 8.0Hz), 7.24 (m, 2H), 7.36 (m, 2H), 7.49 (d, 1H, J = 7.6 Hz), 7.71 (br s,1H), 7.80 and 7.85 (two s, 1H, J = 8.0 Hz), 8.12 and 8.45 (two s, 1H)1302

tert-butyl (4-(1-hydroxy-2-(5H- imidazo[5,1-a]isoindol-5-yl)ethyl)phenyl)carbamate 81 ¹H NMR (a mixture of diastereomers) 1.50(s, 9H), 2.28-2.41 (m, 2H), 4.98-5.03 (m, 1H), 5.25 and 5.55 (two m,1H), 6.55 and 6.61 (two s, 1H), 7.12-7.54 (m, 7H), 7.66 and 7.78 (two s,1H) 1367

tert-butyl (3-(1-hydroxy-2-(5H- imidazo[5,1-a]isoindol-5-yl)ethyl)phenyl)carbamate 52 ¹H NMR (a mixture of diastereomers)(MeOH-d₄) 1.51 (s, 9H), 2.33-2.57 (m, 2H), 4.93- 4.96 (m, 1H), 5.36 and5.49 (two m, 1H), 7.00-7.06 (m, 2H), 7.19-7.40 (m, 4H), 7.48 (s, 1H),7.53-7.57 (m, 2H), 7.72 (s, 1H) 1349

2-(5H-imidazo[5,1-a]isoindol-5-yl)-1- phenylethanol 73 ¹H NMR (a mixtureof diastereomers) 2.30 (m, 1H), 2.41 (in, 1H), 5.08 (m, 1H), 1H), 7.08(m, 1H), 7.20-7.51 (m, 9 H), 7.63 (s, 1H). 1363

tert-butyl 4-(1-hydroxy-2-(5H- imidazo[5,1-a]isoindol-5-yl)ethyl)piperidine-1-carboxylate 83 ¹H NMR (a mixture of diastereomers)1.26 (m, 2H), 1.44 (s, 9 H), 1.47-1.59 (m, 2H), 1.76 (m, 1H), 206-2.11(m, 1H), 2.14-2.20 (m, 1H), 2.64 (m, 2H), 3.73 and 3.80 (two m, 1H),4.16 (m, 2H), 5.37 and 5.51 (two m, 1H), 7.16 (s, 1H), 7.22 (m, 1H),7.32-7.41 (m, 2H), 7.54 (d, 1H, J = 4.0 Hz), 7.79 and 7.81 (two s, 1H)1357

1-cyclohexyl-2-(6-fluoro-5H- imidazo[5,1-a]isoindol-5-yl)ethanol 96 ¹HNMR (a mixture of diastereomers) 0.98-1.39 (m, 6H), 1.65-1.79 (m, 5H),2.03-2.07 (m, 1H) 2.34-2.50 (m, 2H), 3.54-3.73 (m, 1H), 5.46 and 5.67(two dd, 1H, J = 3.0, 8.0 Hz, J₂ = 3.0, 10.4 Hz), 6.93 (t, 1H, J = 8.0Hz), 7.17 (d, 1H, J = 7.17 Hz), 7.30-7.37 (m, 2H), 7.82, 7.88 (two s,1H) 1359

2-(7-chloro-5H-imidazo[5,1- a]isoindol-5-yl)-1-cyclohexylethanol 98 ¹HNMR (a mixture of diastereomers)1.00-1.28 (m, 5H), 1.37-1.40 (m, 1H),1.66-2.01 (m, 5H), 1.91-2.0 (m, 1H) 2.12-2.23 (m, 1H), 3.71-3.75 (m,1H), 7.15 (s, 1H), 7.33 (d, 1H, J = 8.0 Hz), 7.45 (d, 1H, J = 8.0 Hz),7.79, 7.82 (two s, 1H) 1362

1-cyclopentyl-2-(5H-imidazo[5,1- a]isoindol-5-yl)ethanol 91 ¹H NMR (amixture of diastereomers) 1.11-1.41 (m, 2H), 1.55-1.70 (m, 4H),1.83-2.17 (m, 4H), 3.74-3.79 (m, 1H), 5.38, 5.49 (one t and one d, 1H, J= 6.0 Hz, J₂ = 6.0 Hz), 7.18 (s, 1H), 7.25 (d merged with CHCl₃, 1H),7.38 (t, 1H, J = 7.2 Hz), 7.46 (d, 1H, J = 7.6 Hz), 7.55 (d, 1H, J = 7.6Hz), 7.84 (s, 1H) 1375

1-(cyclohex-1-en-1-yl)-2-(5H- imidazo[5,1-a]isoindol-5-yl)ethanol 92 ¹HNMR (a mixture of diastereomers) 1.47-1.68 (m, 3H), 1.73-1.82 (m, 1H),1.93-2.14 (m, 4H), 2.18-2.22 (m, 1H), 2.33-2.40 (m, 2H), 4.36 (t, 1H, J= 7.0 Hz), 5.26, 5.44 (one t and one dd, 1H, J₁ = 6.0 Hz, J₂ = 10.0 Hz),5.71, 5.72 (two s, 1H), 7.15, 7.18 (two, s, 1H), 7.2-7.26 (m, 1H), 7.34,7.38 (two d, 1H, J₁ = 6.8 Hz, J₂ = 7.27 Hz), 7.43 (d, 1H, J = 7.6 Hz),7.54 (d, 1H, J = 7.6 Hz), 7.81, 7.86 (two s, 1H) 1343

1-(3-chlorophenyl)-2-(5H-imidazo[5,1- a]isoindol-5-yl)ethanol 59 ¹H NMR(a mixture of diastereomers) 2.18-2.52 (m, 2H), 5.25-5.40 (m, 1H),5.46-5.60 (m, 1H), 7.07 (s, 1H), 7.15-7.55 (m, 7H), 7.69 (d, 1H, J = 8.0Hz), 7.79 (s, 1H) 1336

1-(2-chlorophenyl)-2-(5H-imidazo[5,1- a]isoindol-5-yl)ethanol 45 ¹H NMR(a mixture of diastereomers) 2.20-2.50 (m, 2H), 5.0-5.08 (m, 1H),5.26-5.38 (m, 1H), 7.05 (s, 1H), 7.20-7.45 (m, 7H), 7.45 (d, 1H, J = 7.6Hz), 7.52 (d, 1H, J = 7.6 Hz) 7.68 (s, 1H) 1374

2-(8-chloro-5H-imidazo[5,1- a]isoindol-5-yl)-1-cyclohexylethanol 41 ¹HNMR (a mixture of diastereomers) (MeOH-d₄) 1.00-2.30 (m, 13H), 3.60-3.70(m, 1H), 5.35 and 5.50 (two m, 1H), 6.95-7.08 (m, 1H), 7.16-7.88 (m, 4H)1376

1-cyclohexyl-2-(8-fluoro-5H- imidazo[5,1-a]isoindol-5-yl)ethanol 15^(\1)H NMR (a mixture of diastereomers) (MeOH-d₄) 1.00-2.30 (m, 13H),3.50-3.57 (m, 1H), 5.35 and 5.50 (m, 1H), 7.18-7.50 (m, 3H), 7.60-7.65(m, 1H), 7.92 and 7.98 (two s, 1H) 1378

2-(6-fluoro-5H-imidazo[5,1- a]isoindol-5-yl)-1-(1,4-dioxaspiro[4.5]decan-8-yl)ethanol 90 ¹H NMR (a mixture of diastereomers)(MeOH-d₄) 1.31-1.52 (m, 5H), 1.60-1.63 (m, 1H), 1.71-1.78 (m, 3H),1.86-2.07 (m, 1H), 2.43-2.48 (m, 1H), 3.48-3.64 (m, 1H), 3.90 (s, 4H)5.57 and 5.69 (two m, 1H), 7.00-7.06 (m, 1H), 7.18 (d, 1H, J = 11.6 Hz),7.41-7.44 (m, 2H), 7.94-8.00 (m, 2H) 1358

2-(5H-imidazo[5,1-a]isoindol-5-yl)-1- (tetrahydro-2H-pyran-4-yl)ethanol92 ¹H NMR (a mixture of diastereomers)1.39-1.51 (m, 2H), 1.59-1.65 (m,1H), 1.71-1.75 (m, 1H), 2.11-2.17 (m, 1H), 3.32-3.39 (m, 3H), 3.69-3.73(m, 1H), 3.96-4.05 (m, 3H), 5.39 and 5.49 (two m, 1H), 7.17 (s, 1H),7.23-7.28 (m, 1H), 7.33-7.44 (m, 2H), 7.55 (d, 1H, J = 8Hz), 7.84 (s,1H) 1372

1-cyclohexyl-2-(9-methoxy-5H- imidazo[5,1-a]isoindol-5-yl)ethanol 83 ¹HNMR (a mixture of diastereomers) (CD₃OD) 1.05-1.11 (m, 1H), 1.13-1.33(m, 4H), 1.58-1.81 (m, 5H), 2.01-2.08 (m, 1H), 3.57 and 3.67 (two m,1H), 3.95 (s, 3H), 5.40 and 5.47 (two m, 1H), 6.81 and 6.83 (two d, 1H,J = 8 Hz), 6.90 and 6.97 (two d, 1H, J = 7.6 Hz), 7.04 and 7.05 (two s,1H), 7.12-7.17 (m, 1H), 7.92 and 7.99 (two s, 1H). 1352

1-(2,5-dimethylfuran-3-yl)-2-(6-fluoro- 5H-imidazo[5,1-a]isoindol-5-yl)ethanol 81 ¹H NMR (a mixture of diastereomers) 1.89-1.96, 2.37-2.45,2.53-2.59, 2.77-2.83 (four m, 2H), 2.11, 2.17 (s, 3H), 2.20, 2.22 (twos, 3H), 4.79-4.88 (m, 1H), 5.36-5.68, 5.63-5.64 (two m, 1H), 5.94, 5.97(two s, 1H), 6.87-6.97 (m, 1H), 7.15, 7.21 (two s, 1H), 7.32-7.38 (m,2H), 7.74, 7.88 (two s, 1H) 1393

2-(6-fluoro-5H-imidazo[5,1- a]isoindol-5-yl)-1-(furan-2-yl)ethanol 88 ¹HNMR (a mixture of diastereomers) 1.99-2.06, 2.36-2.43 (two m, 1H),2.77-2.80, 2.92- 2.98 (two m, 1H), 3.72 (d, 1H, J = 11.0 Hz), 5.02-5.08(m, 1H), 5.39-5.40, 5.67-5.69 (two m, 1H), 6.27 (t, 1H, J = 6.4 Hz),6.31 (s, 1H), 6.93 (s, 1H, J = 9.2 Hz), 7.08 (d, 1H, J = 12.2 Hz),7.26-7.36 (m, 2H), 7.77, 7.86 (two s, 1H) 1394

2-(6-fluoro-5H-imidazo[5,1- a]isoindol-5-yl)-1-(1-methyl-1H-imidazol-2-yl)ethanol 81 ¹H NMR (a mixture of diastereomers)2.43-2.51,2.81-2.85, 2.99-3.15 (three m, 2H), 3.69 (s, 3H), 5.00-5.08 (m, 1H),5.38-5.40, 5.67-5.69 (two m, 1H), 6.77 (s, 1H), 6.79 (s, 1H), 6.91 (t,1H, J = 8.9 Hz), 7.07 (s, 1H), 7.28-7.33 (m, 2H), 7.79 (s, 1H) 1390

2-(5H-imidazo[5,1-a]isoindol-5-yl)-1- (thiazol-4-yl)ethanol 34 ¹H NMR (amixture of diastereomers)2.14-2.21, 2.49-2.58, 2.68-2.82 (m, 2H),5.23-5.53 (m, 2H), 7.11 (s, 1H), 7.21 (s, 1H), 7.25-7.28 (m, 1H, overlapwith CHCl3), 7.37 (t, 1H, J = 7.5 Hz), 7.47-7.54 (m, 2H), 7.74 (s, 1H),8.79 (s, 1H) 1407

1-(4,4-difluorocyclohexyl)-2-(5H- imidazo[5,1-a]isoindol-5-yl)ethanol 61¹H NMR (a mixture of diastereomers)1.26-1.36 (m, 3H), 1.63-1.97 (m, 5H),2.02-2.08 (m, 3H), 3.69-3.72 (m, 1H), 5.02 and 5.12 (two d, 1H, J = 6.0Hz), 5.34-5.53 and 5.41- 5.43 (two m, 1H), 7.10 and 7.12 (two s, 1H),7.25 (t, 1H, J = 7.4 Hz), 7.36 (t, 1H, J = 7.4 Hz), 7.54-7.58 (m, 2H),7.91 and 7.93 (two s, 1H 1406

1-(4,4-difluorocyclohexyl)-2-(6-fluoro- 5H-imidazo[5,1-a]isoindol-5-yl)ethanol 78 ¹H NMR (a mixture of diastereomers) (DMSO-d₆): 1.21-1.29(m, 3H), 1.56-1.72 (m, 4H) 1.88-1.96 (m, 3H), 2.28 and 2.32 (two t, 1H,J = 5Hz), 3.41-3.44 and 3.62-3.65 (two m, 1H), 4.73 and 5.17 (two d, 1H,J = 8.2 Hz), 5.56-5.59 and 5.61-5.64 (two m, 1H), 7.03- 7.17 (m, 2H),7.39-7.44 (m, 2H), 7.91 and 7.95 (two s, 1H) 1414

1-(cyclohex-3-enyl)-2-(6-fluoro-5H- imidazo[5,1-a]isoindol-5-yl)ethanol74 ¹H NMR (a mixture of diastereomers)1.21-1.42 (m, 2H), 1.62-1.83 (m,4H), 1.93-2.15 (m, 7H), 2.30-2.44 (m, 1H), 2.6 (brs, 1H), 3.67-3.72 (m,1H), 3.77-3.82 (m, 1H), 5.49 (q, 1H, J = 5.3 Hz), 5.64-5.70 (m, 3H),6.92-6.96 (m, 2H), 7.16-7.19 (m, 2H), 7.31-7.38 (m, 3H), 7.77-7.79 (m,1H), 7.88 (d, 1H, J = 3.6 Hz), 7.91 (s, 1H) 1386

2-(5H-imidazo[5,1-a]isoindol-5-yl)-1- (4-methylenecyclohexyl)ethanol 70¹H NMR (a mixture of diastereomers)1.11-1.20 (m, 2H), 1.49-1.55 (m, 1H),1.74-1.78 (m, 1H), 1.90-2.10 (m, 4H), 2.16-2.23 (m, 1H), 2.31-2.38 (m,2H), 3.74-3.77 and 3.80- 3.85 (two m, 1H), 4.62 (d, 2H, J = 0.8 Hz),5.37 and 5.48(t and dd, 1H, J = 6 Hz and J = 3 Hz, 10.4 Hz), 7.18 (s,1H), 7.23 (dd, 1H, J = 1.2 Hz, 7.6 Hz), 7.37 (t, 1H, J = 7.6 Hz), 7.43(d, 1H, J = 7.6 Hz), 7.55 (d, 1H, J = 7.6 Hz), 7.77 and 7.79 (two s, 1H)1381

2-(6-fluoro-5H-imidazo[5,1- a]isoindol-5-yl)-1-(1,4-dioxaspiro[4.5]decan-8-yl)ethanol 90 ¹H NMR (a mixture of diastereomers)(CD₃OD) 1.20-2.00 (m, 2H), 1.38-1.60 (m, 1H), 1.70-1.80 (m, 1H),1.87-2.09 (m, 6H), 3.30-3.34 and 3.53-3.78 (two m, 1H), 5.56-5.58 and5.69-5.71 (two m, 1H), 7.00-7.04 (m, 1H), 7.42 and 7.62 (m and s, 2H),7.93 and 8.00 (two s, 1H) 1387

2-(6-fluoro-5H-imidazo[5,1- a]isoindol-5-yl)-1-(4-methylcyclohexyl)ethanol 68 ¹H NMR (a mixture of diastereomers)0.81-0.95(m, 3H), 1.20-1.83 (m, 10H), 1.85-2.03 (m, 1H), 2.35-2.52 (m, 1H),3.45-3.80 (m, 1H), 5.50-5.60 and 5.65-5.71 (two m, 1H), 6.98-7.06 (m,1H), 7.14 and 7.18 (two s, 1H), 7.30-7.42 (m, 2H), 7.93 and 7.98 (two s,1H) 1398

2-(6-fluoro-5H-imidazo[5,1- a]isoindol-5-yl)-1-(4-(iodomethylene)cyclohexyl)ethanol 77 ¹H NMR (a mixture ofdiastereomers)0.92-1.45 (m, 2H), 1.54-1.76 (m, 2H), 1.80-2.11 (m, 3H),2.33-3.10 (m, 4H), 3.59-3.90 (m, 1H), 4.60 (s, 1H), 5.45-5.81 (m, 1H),6.91-6.95 (m, 1H), 7.16 (s, 1H), 7.26-7.31 (m, 2H), 7.81-7.83 (m, 1H)1413

2-(9-fluoro-5H-imidazo[5,1- a]isoindol-5-yl)-1-(4-methylcyclohexyl)ethanol 35 ¹H NMR (a mixture of diastereomers) (CD₃OD)0.75-0.96 (m, 3H), 1.00-1.25 (m, 1H), 1.28-1.74 (m, 9H), 2.01-2.14 (m,2H), 3.67-3.80 (m, 1H), 5.49-5.59 (m, 1H), 7.10-7.18 (m, 2H), 7.60-8.00(m, 1H) 1411

2-(6-fluoro-5H-imidazo[5,1- a]isoindol-5-yl)-1-(4-(propan-2-ylidene)cyclo- hexyl)ethanol 77 ¹H NMR (a mixture ofdiastereomers)1.01-1.06 (m, 2H), 1.46-1.57 (m, 2H), 1.63 (s, 6H),1.68-1.75 (m, 2H), 1.82-1.96 (two m, 1H), 2.03-2.11 (m, 1H), 2.32-2.39(two m, 1H), 2.45-2.51 and 2.66-2.75 (two m, 2H), 3.65-3.75 (m, 1H),5.44-5.65 (two m, 1H), 6.91 (t, 1H, J = 8.7 Hz), 7.16 and 7.17 (two s,1H), 7.28-7.36 (m, 2H), 7.80 and 7.87 (two s, 1H) 1410

1-(4- (cyclopropylmethylene)cyclohexyl)-2-(6-fluoro-5H-imidazo[5,1-a]isoindol- 5-yl)ethanol 75 ¹H NMR (a mixtureof diastereomers)0.24 (s, 2H), 0.65 (d, 2H, J = 7.4 Hz), 1.12-1.20 (m,2H), 1.44-1.54 (m, 2H), 1.71-2.03 (m, 6H), 2.34-2.54 (two m, 1H),2.72-2.84 (m, 1H), 3.63-3.80 (m, 1H), 4.48 (d, 1H, J = 9.0 Hz),5.43-5.67 (two m, 1H), 6.81-6.94 (m, 1H), 7.15 (s, 1H), 7.15-7.30 (m,3H), 7.80 and 7.88 (two s, 1H) 1392

1-(4-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)piperidin-1-yl)- 2,2-dimethylpropan-1-one 77 ¹HNMR(a mixture of diastereomers)1.24 (s, 9H), 1.28 (m, 2H), 1.60 (m, 2H),2.13-1.86 (m, 3H), 2.70 (m, 2H), 3.78 (m, 1H), 4.46 (m, 2H), 5.53 and5.38 (two m, 1H), 7.12 (s, 1H), 7.21 (m, 1H), 7.33 (m, 1H), 7.42 (d, 1H,J = 7.5 Hz), 7.52 (d, 1H, J = 7.5 Hz), 7.81 and 7.79 (two s, 1H), 1409

2-(6-fluoro-5H-imidazo[5,1- a]isoindol-5-yl)-1-(1-methyl-1H-imidazol-5-yl)ethanol 44 ¹H NMR(a mixture of diastereomers)1.92-2.42(three m, 1H), 2.72-3.10 (three m, 1H), 3.72 (s, 3H), 4.90-5.10 (threem, 1H), 5.42-5.76 (three m, 1H), 6.77-6.92 (m, 2H), 7.07 and 7.13 (twos, 1H), 7.25-7.37 (m, 3H), 7.82, 7.88 and 7.94 (three s, 1H) 1389

2-(5H-imidazo[5,1-a]isoindol-5-yl)-1- (1-methyl-1H-imidazol-4-yl)ethanol94 ¹H NMR (a mixture of diastereomers)2.01, 2.51, 2.67 (three m, 2H),3.61 (s, 3H), 5.09 and 5.00 (two m, 1H), 5.53 and 5.33 (two m, 1H), 6.75and 6.70 (two s, 1H), 7.11 (s, 1H), 7.25-7.16 (m, 2H), 7.32 (m, 1H),7.37 (s, 1H), 7.49 (t, 1H, J = 7.80 Hz), 7.88 and 7.67 (twos, 1H), 1391

2-(5H-imidazo[5,1-a]isoindol-5-yl)-1- (thiazol-5-yl)ethanol 75 ¹H NMR (amixture of diastereomers)1.84, 2.03, 2.45, 2.51, 2.66, (five m, 2H),5.29 5.41, 5.55 (three m, 2H), 7.06-7.28 (m, 2H), 7.37 (t, 1H, J = 7.5Hz), 7.41 (d, 1H, J = 7.5Hz), 7.52 (d, 1H, J = 7.5 Hz), 7.71, 7.73 (twos, 1H), 7.83 (s, 1H), 8.70, 8.71 (two s, 1H), 1385

1-(4-(1-hydroxy-2-(5H-imidazo[5,1- a]isoindol-5-yl)ethyl)piperidin-1-yl)ethanone 93 ¹H NMR (a mixture of diastereomers) 1.28 (m, 2H), 1.62(m, 2H), 1.83 (m, 1H), 2.04 and 2.06 (two s, 3H), 2.19 (m, 1H), 2.47 (t,1H, J = 12.4 Hz), 3.00 (t, 1H, J = 13.1 Hz), 3.74 (m, 1H), 3.84 (t, 1H,J = 15.5 Hz), 4.68 (d, 1H, J = 14.6 Hz), 5.37 and 5.51 (two m, 1H), 7.15(s, 1H), 7.23 (m, 1H), 7.39 (m, 2H), 7.54 (d, 1H, J = 7.5 Hz), 7.80 (s,1H) 1384

(4-(1-hydroxy-2-(5H-imidazo[5,1- a]isoindol-5-yl)ethyl)piperidin-1-yl)(thiophen-2-yl)methanone 72 ¹H NMR (a mixture of diastereomcrs)1.39(m, 2H), 1.66 (m, 2H), 2.07 (m, 1H), 2.17 (m, 1H), 2.89 (m, 2H), 3.76(m, 1H), 5.37 and 5.51 (m, 1H), 7.01 (t, 1H, J = 4.3 Hz), 7.16 (s, 1H),7.24 (m, 2H), 7.31-7.40 (m, 3H), 7.54 (d, 1H, J = 7.6 Hz), 7.81 (s, 1H)1405

1-(4-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)piperidin-1-yl)-2- phenylethanone 68 ¹H NMR(amixture of diastereomers)1.00-2.25 (m, 6H), 2.47 (t, 1H, J = 9.8 Hz),2.47 (t, 1H, J = 9.8 Hz), 2.89 (t, 1H, J = 12.0 Hz), 3.70 (m, 3H), 3.90(t, 1H, J = 12.6 Hz), 3.90 (t, 1H, J = 12.3 Hz), 5.25-5.50 (m, 1H),7.10-7.30 (m, 9H), 7.36 (t, 1H, J = 9.6 Hz), 7.53 (d, 1H, J = 7.8 Hz)1404

1-cyclohexyl-3-(5H-imidazo[5,1- a]isoindol-5-yl)propan-2-ol 85 ¹H NMR(amixture of diastereomers)0.80-1-85 (m, 14H), 2.00-2.20 (m, 1H),4.20-4.50 (m, 1H), 5.30-5.60 (m, 1H), 7.14 (s, 1H), 7.20-7.39 (m, 2H),7.43 (d, 1H, J = 7.2 Hz), 7.43 (d, 1H, J = 7.2 Hz), 7.91 (s, 1H) 1403

1-cyclohexyl-3-(6-fluoro-5H- imidazo[5,1-a]isoindol-5-yl)propan-2- ol 55¹H NMR (a mixture of diastereomers)0.55-1.75 (m, 13H), 2.00-2.50 (m,2H), 3.75-4.10 (m, 1H), 5.30-5.75 (m, 1H), 6.85-7.00 (m, 1H), 7.10-7.25(m, 2H), 7.25-7.40 (m, 2H), 7.93 (s, 1H) 1419

1-cyclohexyl-2-(5H-imidazo[5,1- a]isoindol-5-ylidene)ethanol 72 ¹H NMRmixture of E/Z isomers: 1.15-1.30 (m, 10H), 1.66-1.83 (m, 10H),2.00-2.12 (m, 2H), 4.56 (t, 1H, J = 6.4 Hz), 4.66 (d, 1H, J = 7.4 Hz),6.02 (d, 1H, J = 8.3 Hz), 6.76 (s, 1H), 7.07 (s, 1H), 7.33-7.48 (m, 4H),7.56 (d, 2H, J = 7.8 Hz), 7.82 (s, 1H), 7.98 (d, 1H, J = 7.9 Hz), 8.04(s, 1H), 8.42 (s, 1H). 1426

(trans)-methyl 4-((1R)-1-hydroxy-2- (5H-imidazo[5,1-a]isoindol-5-yl)ethyl)cyclohexanecarboxylate 87 ¹H NMR (a mixture of diastereomers)1.05-1.20 (m, 2H), 1.42 (qt, J = 12.7, 4.0 Hz, 3H), 1.63-1.82 (m, 1H),1.92-2.10 (m, 4H), 2.11-2.31 (m, 2H), 3.65 (s, 3H), 3.72- 3.83 (m, 1H),5.36 (t, J = 6.2 Hz, 0.7H), 5.52 (dd, J = 10.8, 3.1 Hz, 0.3H), 7.14 (s,1H), 7.23 (t, J = 7.4 Hz, 1H), 7.31-7.40 (m, 1H), 7.42 (d, J = 7.7 Hz,1H), 7.53 (d, J = 7.6 Hz, 1H), 7.83 (s, 1H) 1438

2-(5H-imidazo[5,1-a]isoindol-5-yl)-1- (spiro[2.5]octan-6-yl)ethanol 46¹H NMR (a mixture of diastereomers) 0.14-0.28 (m, 4H), 0.89 (t, 2H, J =12.0 Hz), 1.19- 2.938(m, 9H), 2.81 (br s, 1H), 3.80-3.82 (m, 1H),5.36-5.39 and 5.50-5.53 (two m, 1H), 7.16 (s, 1H), 7.21-7.25 (m, 1H),7.33 (t, 1H, J = 7.6 Hz), 7.44 (d, 1H, J = 7.6 Hz), 7.53 (d, 1H, J = 7.6Hz), 7.80 and 7.81 (two s, 1H ) 1475

(trans)-4-(2-(6-fluoro-5H-imidazo[5,1- a]isoindol-5-yl)-1-hydroxyethyl)cyclohexanol 92 ¹H NMR (a mixture of diastereomers)1.07-2.52 (m, 11H), 3.48-3.68 (two m, 2H), 5.45 (t, 1H, J = 6.0 Hz),5.65 (dd, 1H, J = 9.0, 3.0 Hz), 6.89-6.96 (m, 1H), 7.16 (s, 1H), 7.29-7.38 (m, 2H), 7.80 and 7.88 (two s, 1H) 1499

(1R)-1-((trans)-4- (benzyloxy)cyclohexyl)-2-(6-fluoro-5H-imidazo[5,1-a]isoindol-5- yl)ethanol 65 ¹H NMR (a mixture ofdiastereomers) 1.04-1.33 (m, 5H), 1.71-2.32 (m, 5H), 2.75-2.51 (two m,1H), 3.24-3.29 (m, 1H), 3.65-3.69 (m, 1H), 4.54 (s, 2H), 5.43 (t, 1H, J= 4.7 Hz, isomer), 5.65 (dd, 1H, J = 10.4, 2.4 Hz, isomer), 6.92 (t, 1H,J = 8.8 Hz), 7.14 (s, 1H), 7.26-7.33 (m, 7H), 7.79 and 7.88 (two s, 1H)1498

(1R)-1-((trans)-4- (benzyloxy)cyclohexyl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethanol 78 ¹H NMR (a mixture ofdiastereomers) 1.15-2.20 (m, 11H), 3.22-3.31 (m, 1H), 3.65-3.75 (m, 1H),4.48 and 4.54 (two s, 2H), 5.35 (t, 1H, J = 8.0 Hz, isomer), 5.48 (dd,1H, J = 16.0, 4.0 Hz, isomer), 7.15-7.55 (m, 10H), 7.77 and 7.79 and7.81 (three s, 1H) 1492

N-((cis)-4-(1-hydroxy-2-(5H- imidazo[5,1-a]isoindol-5-yl)ethyl)cyclohexyl)benzamide 63 ¹H NMR (a mixture of diastereomers)(CD₃OD) 1.27-1.46 (m, 5H), 1.79 (d, 1H, J = 12.0 Hz), 2.04-2.22 (m, 5H),3.78-3.88 (m, 2H), 5.47-5.49 and 5.53-5.54 (two m, 1H), 7.16 and 7.19(two s, 1H), 7.35 (t, 1H, J = 7.4 Hz), 7.42-7.49 (m, 3H), 7.53 (d, 1H, J= 7.2 Hz), 7.59 (d, 1H, J = 7.6 Hz), 7.64 (d, 1H, J = 7.6 Hz), 7.82 (d,2H, J = 7.6 Hz), 7.97 and 8.01 (two s, 1H) 1505

N-((trans)-4-(1-hydroxy-2-(5H- imidazo[5,1-a]isoindol-5-yl)ethyl)cyclohexyl)benzamide 57 ¹H NMR (a mixture of diastereomers)1.14-1.45 (m, 4H), 1.74 (d, 1H, J = 10.6 Hz), 1.97 (d, 1H, J = 10.6 Hz),2.09-2.20 (m, 4H), 3.71-3.82 (m, 1H), 3.85-3.95 (m, 1H), 5.3-5.40 and5.48-5.59 (two m, 1H), 6.03 (d, 1H, J = 7.6 Hz), 7.17 (s, 1H), 7.21-7.30(m, 1H, merged with chloroform), 7.31-7.51 (m, 5H), 7.55 (d, 1H, J = 7.4Hz), 7.74 (d, 2H, J = 7.6 Hz), 7.83 (s, 1H) 1441

1-(4-(2- hydroxyethylidene)cyclohexyl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethanol 59 ¹H NMR (a mixture ofdiastereomers) 1.00-1.30 (m, 2H), 1.40-1.60 (m, 1H), 1.62-1.81 (m, 2H),1.82-2.13 (m, 3H), 2.60-2.75 (m, 1H), 3.60-3.75 (m, 1H), 3.90-4.10 (m,2H), 5.25-5.31 (m, 1H), 5.33-5.48 (m, 1H), 7.13 (s, 1H), 7.20-7.43 (m,2H), 7.46-7.60 (m, 2H 7.97 (s, 1H) 1460

tert-buty 3-(1-hydroxy-2-(5H- imidazo[5,1-a]isoindol-5-yl)ethyl)azetidine-1-carboxylate 43 ¹H NMR (a mixture of diastereomers)1.42 (s, 9H), 1.92-2.23 (m, 2H), 2.50-2.63 (m, 1H), 3.61-3.80 (m, 2H),3.90-4.02 (m, 3H), 4.20-4.58 (br, 1H), 5.33-5.41 and 5.52-5.58 (two m,1H), 7.13 (s, 1H), 7.21-7.28 (m, 1.58H), 7.30-7.39 (m, 1.33H), 7.41-7.48(m, 0.8H), 7.58 (d, J = 14.3 Hz, 1H), 7.93 and 7.99 (two s, 1H) 1502

2-(5H-imidazo[5,1-a]isoindol-5-yl)-1- (pyridin-2-yl)ethanol 82 ¹H NMR (amixture of diastereomers) 2.25-2.33 (m, 2H), 5.06-5.07 (m, 1H), 5.09 (brs, 1H), 5.35-5.38 and 5.46-5.49 (two m, 1H), 7.02 (s, 1H), 7.13-7.24 (m,4H), 7.44-7.48 (m 2H), 7.57-7.62 (m, 2H)3 8.46-8.47 (m, 1H) 1474

2-(5H-imidazo[5,1-a]isoindol-5-yl)-1- (pyridin-3-yl)ethanol 69 ¹H NMR (amixture of diastereomers) 1.75-2.43 (m, 2H), 5.07-5.12 (m, 1H),5.38-5.40 and 5.56-5.58 (two m, 2H), 6.98 and 7.11 (two s, 1H),7.19-7.33 (m, 3H), 7.43-7.49 (m, 2H), 7.43-7.79 (m, 2H), 8.3-8.51 (m,2H) 1501

2-(5H-imidazo[5,1-a]isoindol-5-yl)-1- (pyridin-4-yl)ethanol 30 ¹H NMR (amixture of diastereomers) 1.98-2.32 (m, 2H), 3.59 (br, 1H), 5.03-5.06(m, 1H), 5.42-5.45 and 5.56-5.58 (two m, 1H), 7.20-7.23 (m, 1H),7.24-7.25 (m, 4H), 7.34 (t, J = 7.0 Hz, 1H), 7.41 (d, J = 7.2 Hz, 1H),7.49 (d, J = 7.6 Hz, 1H), 8.44-8.46 (m, 2H) 1509

2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(4-(trifluoromethyl)cyclohexyl)ethanol 69 ¹H NMR (a mixture ofdiastereomers) 1.53-2.22 (m, 12H), 3.92-3.98 (m, 1H), 4.12 (br s, 1H),5.39-5.43 and 5.50-5.60 (two m, 1H), 7.14 (s, 1H), 7.23-7.54 (m, 5H),7.94 (s, 1H) 1508

2-(6-fluoro-5H-imidazo[5,1- a]isoindol-5-yl)-1-(4-(trifluoromethyl)cyclohexyl)ethanol 61 ¹H NMR (a mixture ofdiastereomers) 1.40-1.70 (m, 7H), 1.70-1.90 (m, 2H), 1.91-2.04 (m, 1H),2.09-2.28 (m, 1H), 2.38-2.48 (m, 1H), 3.80-3.98 (br, 2H), 5.43-5.71 (twom, 1H), 6.91-6.94 (m, 1H), 7.14 (s, 1H), 7.29-7.38 (m, 2H), 7.93 and7.97 (two s, 1H) 1473

l-((cis)-4-(benzyloxy)cyclohexyl)-2-(6-fluoro-5H-imidazo[5,1-a]isoindol- 5-yl)ethanol 87 ¹H NMR (a mixtureof diastereomers) 1.39-2.42 (m, 12 H), 3.39-3.78 (m, 2H), 4.47 and 4.48(two s, 2H), 5.44 (t, 1H, J = 5.1 Hz), 5.67 (dd, 1H, J = 10.2, 2.8 Hz),6.88-6.94 (m, 1H), 7.25-7.36 (m, 8H), 7.80, 7.82, 7.88 and 7.90 (four s,1H)

Example 26 Preparation of 1469-1472

The pure diastereomers were obtained from the racemic mixture of 1363using preparative chiral supercritical fluid chromatography (SFC)technique, using a AD-H column (Regis Technologies, Inc.) inmethanol:CO₂ (24:76).

Example 27 General Procedure for the Removal of Boc Protecting Group

To a solution of the appropriate Boc protected amine 1363, 1469, 1470,1471, 1472 or 1460 (1.13 mmol) in dichloromethane (10 mL) was addedtrifluoroacetic acid (33.8 mmol). The resulting solution was stirred atRT for 2 h and concentrated. The crude was dissolved in methanol (4 mL)and hydrogen chloride (4M in dioxane) (3.39 mmol) was added. The mixturewas concentrated and dried under high vacuum to give the desired productas a dihydrochloride salt which was directly used in the next stepwithout further purification.

Example 28 General Procedure for the Synthesis of 1423, 1424, 1425,1437, 1439, 1448, 1450, 1458, 1480, 1481, 1490, 1493, 1500 and 1511Using HATU Coupling

To a vial containing appropriate amine salt obtained from Example 27(0.25 mmol) in DMF (4 mL) was added the corresponding carboxylic acid(0.26 mmol), DIPEA (1.5 mmol) and HATU (0.28 mmol). The reaction mixturewas stirred at rt for 18 h and poured into water (10 mL) and the aqueouslayer was extracted with dichloromethane (2×20 mL). The combined organiclayers were washed with water (2×10 mL), dried over Na₂SO₄, andconcentrated. The crude product was purified by flash columnchromatography to afford 1423, 1424, 1425, 1437, 1439, 1448, 1450, 1458,1480, 1481, 1490, 1493 or 1500.

Example 29 General Procedure for the Synthesis of 1449, 1459, 1476,1477, 1478 and 1479

To a vial containing appropriate amine salt obtained from Example 19(0.25 mmol) in dichloromethane (4 mL) was added DIPEA (1.0 mmol) andphenylisocyanate (0.25 mmol). The reaction mixture was stirred at rt for30 min and concentrated. The residue was dissolved in dichloromethane(30 mL) and washed with water (3×10 mL). The organic layer was driedover Na₂SO₄ and concentrated. The crude product was purified by flashcolumn chromatography to afford ureas 1449, 1459, 1476, 1477, 1478 and1479.

Example 30 General Procedure for the Synthesis of 1495, 1496, 1497,1503, 1504, 1507, 1512

To a solution of appropriate amine (0.3 mmol) in CH₂Cl₂ (3 mL) was addedcarbonyldiimidazole (0.35 mmol) and ethyl diisopropylamine (2.0 mmol) at0° C. under an atmosphere of N₂ and the mixture was stirred for 1 h. Theappropriate amine salt obtained from Example 19 (0.25 mmol) was addedand the mixture was allowed to stir overnight. The solution waspartitioned with water in a separatory funnel and the organic layer wascollected. The aqueous layer was extracted with dichloromethane (3×10mL) and the combined organic fractioned were dried (Na₂SO₄). The crudewas purified by flash column chromatography to afford 1495, 1496, 1497,1503, 1504 or 1507.

Yield # Compound Name (%) 1423

1-(4-(1-hydroxy-2-(5H- imidazo[5,1-a]isoindol-5-yl)ethyl)piperidin-1-yl)-2- (pyrimidin-5-yl)ethanone 76 ¹H NMR (amixture of diastereomers) 1.30-1.41 (m, 3H), 1.63-1.72 (m, 2H),1.87-2.22 (m, 2H), 2.56 (t, 1H, J = 12.4 Hz), 3.01-3.15 (m, 2H), 3.67(d, 1H, J = 6.0 Hz), 3.83-3.85 (m, 1H), 3.96 (t, 1H, J = 14.6 Hz), 4.66(t, 1H, J = 14.6 Hz), 5.44-5.46 and 5.62-5.65 (two m, 1H), 7.17 and 7.19(two s, 1H), 7.26-7.30 (m, 1H, merged with chloroform), 7.39 (t, 1H, J =7.4 Hz), 7.46 (d, 1H, J = 7.6 Hz), 7.56 (d, 1H, J = 7.2 Hz), 8.14 (d,1H, J = 13.2 Hz), 8.63 (d, 2H, J = 4.4 Hz), 9.08-9.10 (m, 1H) 1424

2-(3,4-difluorophenyl)-1-(4-(1- hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)piperidin-1- yl)ethanone 71 ¹H NMR (a mixture ofdiastereomers) 1.16-1.33 (m, 2H), 1.61-1.64 (m, 3H), 1.84-1.92 (m, 1H),2.09-2.15 (m, 1H), 2.53 (t, 1H, J = 12.8 Hz), 2.98 (t, 1H, J = 12.8 Hz),3.67 (d, 2H, J = 4.0 Hz), 3.76-3.78 (m, 1H), 3.90 (t, 1H, J = 13.6 Hz),4.19 (br s, 1H), 4.70 (t, 1H, J = 13.6 Hz), 5.32-5.36 and 5.49-5.53 (twom, 1H), 6.94 (s, 1H), 7.06-7.13 (m, 2H), 7.14 (s, 1H), 7.24-7.30 (m,1H), 7.34-7.42 (m, 2H), 7.56 (d, 1H, J = 6.8 Hz), 7.81-7.85 (m, 1H) 1425

cyclohexyl(4-(1-hydroxy-2-(5H- imidazo[5,1-a]isoindol-5-yl)ethyl)piperidin-1-yl)methanone 44 ¹H NMR (a mixture of diastereomers)1.20-1.34 (m, 6H), 1.49-1.77 (m, 10H), 1.87-1.97 (m, 1H), 2.03-2.08 (m,1H), 2.16-2.20 (m, 1H), 2.46 (t, 2H, J = 12.0 Hz), 3.76-3.79 (m, 1H),3.97 (t, 1H, J = 16.2 Hz), 4.70 (t, 1H, J = 14.2 Hz), 5.38-5.41 and5.51-5.56 (two m, 1H), 7.15 (s, 1H), 7.23-7.27 (m, 1H, merged withchloroform), 7.37 (t, 1H, J = 7.8 Hz), 7.44 (d, 1H, J = 7.6 Hz), 7.54(d, 1H, J = 7.6 Hz), 7.79 and 7.82 (two s, 1H) 1437

1-(4-(1-hydroxy-2-(5H- imidazo[5,1-a]isoindol-5-yl)ethyl)piperidin-1-yl)-2- (140yridine-4-yl)ethanone 49 ¹H NMR (amixture of diastereomers) 1.08-1.16 (m, 1H), 1.23-1.33 (m, 1H),1.57-1.65 (m, 2H), 1.86 (t, 1H, J = 14.0 Hz), 1.99-2.17 (m, 2H), 2.52(dt, 1H, J = 2.4, 12.8 Hz), 2.97 (dt, 1H, J = 4.0, 12.8 Hz), 3.70 (d,2H, J = 7.2 Hz), 3.70- 3.76 (m, 1H, merged with doublet at 3.70), 3.83(t, 1H, J = 13.8 Hz), 4.30 (br s, 1H), 4.69 (t, 1H, J = 14.0 Hz), 5.32-5.36 and 5.51-5.53 (two m, 1H), 7.10 and 7.12 (two s, 1H), 7.16-7.25 (m,3H), 7.35-7.41 (m, 2H), 7.54 (d, 1H, J = 7.6 Hz), 7.76 (d, 1H, J = 4.4Hz), 8.49-8.52 (m, 2H) 1439

2-(4-fluorophenyl)-1-(4-(1- hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)piperidin-1- yl)ethanone 80 ¹H NMR (a mixture ofdiastereomers) 1.08-1.13 (m, 1H), 1.23-1.30 (m, 1H), 1.54-1.63 (m, 2H),1.78 and 1.86 (two d, 1H, J = 13.0 Hz), 1.99-2.12 (m, 2H), 2.49 (dt, 1H,J = 2.4, 12.8 Hz), 2.93 (dt, 1H, J = 3.0, 12.8 Hz), 3.66 (d, 2H, J = 4.4Hz), 3.71-3.73 (m, 2H, merged with broad singlet of OH), 3.90 (t, 1H, J= 15.2 Hz), 4.68 (t, 1H, J = 13.6 Hz), 5.30-5.37 and 5.47-5.50 (two m,1H), 6.94-7.00 (m, 2H), 7.13 (s, 1H), 7.15-7.20 (m, 2H), 7.22-7.31 (m,1H, merged with chloroform), 7.35-7.41 (m, 2H), 7.54 (d, 1H, J = 7.6Hz), 7.84 (d, 1H, J = 5.2 Hz) 1448

(3-fluoro-2-hydroxyphenyl)(4-(1- hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)piperidin-1- yl)methanone 26 ¹H NMR 1.35-1.47 (m,2H), 1.66-1.70 (m, 2H), 1.86-2.15 (m, 7H), 2.89 (m, 1H), 4.31 (br s,1H), 5.43-5.47 and 5.53- 5.59 (two m, 1H), 6.78-6.84 (m, 1H), 6.99 (d,1H, J = 7.6 Hz), 7.11 (t, 1H, J = 9.4 Hz), 7.19 (s, 1H), 7.33 (d, 1H, J= 7.2 Hz), 7.37-7.47 (m, 2H), 7.58 (d, 1H, J = 7.2 Hz), 8.03 and 8.13(two s, 1H) 1449

4-(1-hydroxy-2-(5H-imidazo[5,1- a]isoindol-5-yl)ethyl)-N-phenylpiperidine-1-carboxamide 62 ¹H NMR (CD₃OD) 1.33-1.43 (m, 2H),1.59-1.71 (m, 2H), 1.92-1.95 (m, 1H), 2.10-2.22 (m, 2H), 2.87 (t, 2H, J= 11.8 Hz), 3.79-3.83 (m, 1H), 4.25 (t, 2H, J = 15.2 Hz), 5.48 and5.52-5.55 (t, J = 6.0 Hz, and m, 1H), 7.03 (t, 1H, J = 7.4 Hz), 7.16 and7.19 (two s, 1H), 7.28 (t, 2H, J = 8.0 Hz), 7.33-7.37 (m, 3H), 7.43 (t,1H, J = 7.4 Hz), 7.62 (dd, 2H, J = 7.6, 21.6 Hz), 7.94 and 7.97 (two s,1H), 8.01 (s, 1H) 1450

(4-fluorophenyl)(4-(1-hydroxy-2- (5H-imidazo[5,1-a]isoindol-5-yl)ethyl)piperidin-1-yl)methanone 29 ¹H NMR 1.29-1.37 (m, 3H), 1.57-1.87(m, 3H), 2.18-2.36 (m, 2H), 3.73-3.86 (m, 4H), 4.74 (br s, 1H),5.44-5.49 and 5.58-5.63 (two m, 1H), 7.08 (t, 2H, J = 7.2 Hz), 7.23 (s,1H), 7.31-7.48 (m, 5H), 7.59 (d, 1H, J = 7.2 Hz), 8.20 and 8.27 (two s,1H) 1458

1-(3-(1-hydroxy-2-(5H- imidazo[5,1-a]isoindol-5-yl)ethyl)azetidin-1-yl)-2- phenylethanone 55 ¹H NMR (a mixture ofdiastereomers) 1.79-2.13 (m, 2H), 2.44-2.48 (m, 1H), 3.33-3.42 (m, 2H),3.67-3.93 (m, 2H), 3.97-4.04 (m, 2H), 4.12-4.19 (m, 1H), 5.23-5.31 and5.34-5.42 (two m, 1H), 7.08-7.37 (m, 9H), 7.46-7.48 (m, 1 H), 7.93 and8.07 (two d, J = 7.6 Hz, 1H) 1459

3-(1-hydroxy-2-(5H-imidazo[5,1- a]isoindol-5-yl)ethyl)-N-phenylazetidine-1-carboxamide 19 ¹H NMR (a mixture of diastereomers)1.95-2.20 (m, 2H), 2.64-2.68 (m, 1H), 3.76-3.81 (m, 1H), 3.98-4.10 (m,4H), 5.43-5.46 and 5.51-5.57 (two m, 1H), 6.97-7.14 (m, 1H), 7.22 and7.24 (two s, 1H), 7.26-7.38 (m, 3.3H), 7.40-7.42 (m, 3H), 7.57-7.62 (m,1.7H), 7.99 and 8.00 (two s, 1H) 1476

4-((S)-1-hydroxy-2-((R)-5H- imidazo[5,1-a]isoindol-5-yl)ethyl)-N-phenylpiperidine-1-carboxamide 67 ¹H NMR 1.32-1.41 (m, 2H), 1.51-1.57(m, 1H), 1.61 (d, 1H, J = 12.4 Hz), 1.83 (d, 1H, J = 12.4 Hz), 2.00-2.14(m, 2H), 2.78 (t, 2H, J = 12.0 Hz), 3.74-3.76 (m, 1H), 4.15-4.18 (m,2H), 4.42 (br s, 1H), 5.32 (t, 1H, J = 6.0 Hz), 6.98 (t, 1H, J = 7.4Hz), 7.15 (d, 2H, J = 14.4 Hz), 7.20-7.25 (m, 3H), 7.35-7.37 (m, 3H),7.40 (d, 1H, J = 7.6 Hz), 7.52 (d, 1H, J = 7.6 Hz), 7.86 (s, 1H) 1477

4-((R)-1-hydroxy-2-((R)-5H- imidazo[5,1-a]isoindol-5-yl)ethyl)-N-phenylpiperidine-1-carboxamide 78 ¹H NMR 1.15-1.61 (m, 6 H), 1.86 (d,1H, J = 12.8 Hz), 2.17-2.22 (t, J = 11.2 Hz), 2.66-2.75 (m, 2H),3.68-3.76 (m, 1H), 4.04-4.08 (m, 2H), 4.60 (br, 2H), 5.47 (d, 1H, J =8.8 Hz), 6.86-6.90 (t, 1H, J = 11.2 Hz), 6.94 (s, 1H), 7.09-7.31 (m,7H), 7.45 (d, 1H, J = 7.2 Hz), 8.24 (s, 1H) 1478

4-((R)-1-hydroxy-2-((S)-5H- imidazo[5,1-a]isoindol-5-yl)ethyl)-N-phenylpiperidine-1-carboxamide 74 ¹H NMR 1.32-1.61 (m, 4H), 1.81 (d,1H, J = 12.5 Hz), 2.01-2.15 (m, 2H), 2.77 (t, 2H, J = 12.4 Hz),3.68-3.73 (m, 1H), 4.08-4.14 (m, 2H), 5.31 (t, 1H, J = 4.0 Hz), 6.92 (s,1H), 6.97 (t, 1H, J = 6.0 Hz), 7.12 (s, 1H), 7.21-7.38 (m, 6H), 7.51 (d,1H, J = 7.4 Hz), 7.87 (s, 1H) 1479

4-((S)-1-hydroxy-2-((S)-5H- imidazo[5,1-a]isoindol-5-yl)ethyl)-N-phenylpiperidine-1-carboxamide 78 ¹H NMR 1.15-1.61 (m, 6 H), 1.86 (d,1H, J = 12.8 Hz), 2.17-2.22 (t, 1H, J = 11.2 Hz), 2.66-2.75 (m, 2H),3.68-3.76 (m, 1H), 4.04-4.08 (m, 2H), 4.60 (br, 2H), 5.47 (d, 1H, J =8.8 Hz), 6.86-6.90 (t, 1H, J = 11.2 Hz), 6.94 (s, 1H), 7.09-7.31 (m,7H), 7.45 (d, 1H, J = 7.2 Hz), 8.24 (s, 1H) 1480

1-(4-((R)-1-hydroxy-2-((S)-5H- imidazo[5,1-a]isoindol-5-yl)ethyl)piperidin-1-yl)-2- phenylethanone 82 ¹H NMR 1.0-2.14 (m, 8H),2.46 (t, 1H, J = 12 Hz), 2.91 (t, 1H, J = 12 Hz), 3.65-3.72 (m, 3H),3.91 (t, 1H, J = 16 Hz), 4.71 (t, 1H, J = 12 Hz), 7.15-7.56 (m, 9H),7.55 (d, 1H, J = 7.51 Hz), 7.91 (d, 1H, J = 7.7 Hz) 1481

1-(4-((S)-1-hydroxy-((S)-5H- imidazo[5,1-a]isoindol-5-yl)ethyl)piperidin-1-yl)-2- phenylethanone 85 ¹H NMR 1.04-1.27 (m, 2H),1.51-1.67 (m, 3H), 1.81-1.89 (m, 1H), 2.19-2.55 (m, 1H), 2.46-2.52 (m,1H), 2.90 (t, 1H, J = 12.8 Hz), 3.66-3.74 (m, 3H), 3.90 (t, 1H, J = 16.0Hz), 4.62-4.70 (m, 1H), 5.23 (br s, 1H), 5.49 (dd, 1H, J = 2.2, 10.2Hz), 7.12 (s, 1H), 7.18-7.37 (m, 8H), 7.53 (d, 1H, J = 7.5 Hz), 7.92 (d,1H, J = 3.0 Hz) 1490

1-(4-((S)-1-hydroxy-2-((S)-5H- imidazo[5,1-a]isoindol-5-yl)ethyl)piperidin-1-yl)-2- (tetrahydro-2H-pyran-4-yl) ethanone 77 ¹HNMR (CD₃OD) δ 1.06-1.46 (m, 4H), 1.56-1.73 (m, 3H), 1.82-2.08 (m, 3H),2.32 (t, J = 6.4 Hz, 2H), 2.39 (dd, J = 18.4, 7.2 Hz, 1H), 2.54 (t, J =13.0 Hz, 1H), 3.03 (t, J = 12.9 Hz, 1H), 3.40 (t, J = 11.7 Hz, 2H),3.48-3.59 (m, 1H), 3.90 (d, J = 11.5 Hz, 2H), 3.94-4.06 (m, 1H), 4.57(t, J = 14.8 Hz, 1H), 5.71 (d, J = 6.5 Hz, 1H), 7.41-7.52 (m, 2H), 7.55(d, J = 7.3 Hz, 1H), 7.73 (d, J = 7.1 Hz, 1H), 7.90 (s, 1H), 8.57 (s,1H) 1493

1-(4-((S)-1-hydroxy-2-((R)-5H- imidazo[5,1-a]isoindol-5-yl)ethyl)piperidin-1-yl)-2- phenylethanone 63 ¹H NMR 0.49-1.21 (m, 4H),1.44-1.56 (m, 1H), 1.96-2.05 (m, 2H), 2.38-2.47 (m, 1H), 2.80-2.86 (m,1H), 3.58-3.64 (m, 2H), 3.83 (t, J = 13.2 Hz, 1H), 4.62 (t, J = 13.2 Hz,1H), 5.25-5.30 (m, 1H), 7.13-7.24 (m, 7H), 7.29-7.34 (m, 2H), 7.48 (d, J= 7.6 Hz, 1H), 7.94 (br s, 1H) 1495

4-((R)-1-hydroxy-2-((S)-5H- imidazo[5,1-a]isoindol-5-yl)ethyl)-N-((trans)-4- hydroxycyclohexyl)piperidine-1- carboxamide 56 ¹H NMR(CD₃OD) 1.21-1.43 (m, 7H), 1.48-1.66 (m, 2H), 1.81-2.01 (m, 5H), 2.14(ddd, 2H, J = 4.4, 8.4, 10.4 Hz), 2.71 (t, 2H, J = 11.7 Hz), 3.49-3.55(m, 2H), 3.74-3.79 (m, 1H), 4.08 (t, 1H, J = 13.6 Hz), 5.46 (t, 1H, J =6.2 Hz), 7.16 (s, 1H), 7.34 (t, 1H, J = 7.5 Hz), 7.43 (t, 1H, J = 7.3Hz), 7.57 (d, 1H, J = 7.6 Hz), 7.64 (d, 1H, J = 7.6 Hz), 8.00 (s, 1H)1496

4-((S)-1-hydroxy-2-((S)-5H- imidazo[5,1-a]isoindol-5-yl)ethyl)-N-(tetrahydro-2H-pyran-4- yl)piperidine-1-carboxamide 84 ¹H NMR1.16-1.74 (m, 6H), 1.78-2.00 (m, 2H), 2.18-2.37 (m, 1H), 2.70 (t, J =12.7 Hz, 2H), 3.33-3.51 (m, 2H), 3.71- 4.13 (m, 5H), 4.76 (d, J = 7.4Hz, 1H), 5.54 (dd merged with br s, J = 10.6, 2.3 Hz, 3H), 7.13 (s, 1H),7.20-7.38 (m, 3H), 7.51 (d, J = 7.5 Hz, 1H), 7.90 (s, 1H) 1497

4-((S)-1-hydroxy-2-((S)-5H- imidazo[5,1-a]isoindol-5-yl)ethyl)-N-((trans)-4- hydroxycyclohexyl)piperidine- 1-carboxamide 65 ¹H NMR1.08-1.44 (m, 6H), 1.57 (t, J = 12.5 Hz, 2H), 1.67-1.80 (m, 1H), 1.90(dd, J = 24.8, 9.8 Hz, 4H), 2.29 (ddd, J = 14.3, 11.0, 3.1 Hz, 1H), 2.69(t, J = 12.8 Hz, 2H), 3.35 (s, 1H), 3.49 (d, J = 4.4 Hz, 2H), 3.63-3.77(m, 1H), 3.95- 4.19 (m, 2H), 5.50 (dd, J = 9.7, 3.0 Hz, 1H), 6.05 (d, J= 7.8 Hz, 1H), 7.15 (s, 1H), 7.31 (td, J = 7.5, 1.0 Hz, 1H), 7.39 (t, J= 7.4 Hz, 1H), 7.46 (d, J = 7.2 Hz, 1H), 7.60 (d, J = 7.5 Hz, 1H), 7.91(d, J = 8.5 Hz, 1H) 1500

1-(4-((R)-1-hydroxy-2-((S)-5H- imidazo[5,1-a]isoindol-5-yl)ethyl)piperidin-1-yl)-2- (tetrahydro-2H-pyran-4-yl) ethanone 46 ¹HNMR 1.19-1.42 (m, 4H), 1.54-1.67 (m, 4H), 1.86-1.90 (m, 1H), 2.08-2.25(m, 4H), 2.43-2.51 (m, 1H), 2.92-3.01 (m, 1H), 3.39 (t, 2H, J = 11.8Hz), 3.72-3.76 (m, 1H), 3.90-3.99 (m, 3H), 4.70 (m, 1H, J = 9.75 Hz),5.35-5.40 (m, 1H), 7.13 (s, 1H), 7.24-7.27 (m, 1H), 7.35-7.43 (m, 2H),7.54 (d, 1H, J = 7.4 Hz), 7.80 (s, 1H) 1503

4-((R)-1-hydroxy-2-((S)-5H- imidazo[5,1-a]isoindol-5-yl)ethyl)-N-(tetrahydro-2H-pyran-4- yl)piperidine-1-carboxamide 77 ¹H NMR1.29-1.33 (m, 1H), 1.41-1.47 (m, 2H), 1.51-1.61 (m, 1H), 1.62 (d, 1H, J= 12.7 Hz), 1.83 (d, 1H, J = 12.4 Hz), 1.91 (d, 2H, J = 12.4 Hz),2.07-2.26 (m, 2H), 2.73 (t, 2H, J = 12.2 Hz), 3.46 (t, 2H, J = 10.8 Hz),3.73-3.78 (m, 1H), 3.81-3.89 (m, 1H), 3.93-4.05 (m, 4H), 4.40 (d, 1H, J= 7.5 Hz), 4.61 (br s, 2H), 5.41 (t, 1H, J = 5.9 Hz), 7.18 (s, 1H),7.24-7.30 (m, 1H, merged with chloroform), 7.39 (t, 1H, J = 7.5 Hz),7.44 (d, 1H, J = 7.6 Hz), 7.56 (d, 1H, J = 7.6 Hz), 7.92 (s, 1H) 1504

N-cyclohexyl-4-((R)-1-hydroxy-2- ((S)-5H-imidazo[5,1-a]isoindol-5-yl)ethyl)piperidine-1-carboxamide 77 ¹H NMR 0.97-1.23 (m, 3H), 1.26-1.36(m, 4H), 1.48-1.70 (m, 5H), 1.82 (d, J = 13.1 Hz, 1H), 1.93 (d, J = 10.3Hz, 2H), 2.07 (ddd, J = 14.3, 6.8, 2.7 Hz, 1H), 2.14-2.27 (m, 1H), 2.70(td, J = 12.8, 2.5 Hz, 2H), 3.57-3.65 (m, 1H), 3.71-3.81 (m, 1H), 3.97(t, J = 13.2 Hz, 2H), 4.31 (d, J = 7.6 Hz, 1H), 5.39 (t, J = 6.0 Hz,1H), 7.16 (s, 1H), 7.24 (dd, J = 7.6, 1.0 Hz, 1H), 7.37 (t, J = 7.4 Hz,1H), 7.43 (d, J = 7.6 Hz, 1H), 7.55 (d, J = 7.6 Hz, 1H), 7.80 (s, 1H)1507

N-cyclopentyl-4-((R)-1-hydroxy-2- ((S)-5-imidazo[5,1-a]isoindol-5-yl)ethyl)piperidine-1-carboxamide 87 ¹H NMR 1511

1-(4-((R)-1-hydroxy-2-((S)-5H- imidazo[5,1-a]isoindol-5-yl)ethyl)piperidin-1-yl)-2-(4- (trifluoromethyl)phenyl)ethanone 69 ¹HNMR 1.03-1.26 (m, 2H), 1.28-1.39 (m, 2H), 1.56 (q, J = 13.9, 13.1 Hz,2H), 1.75 (d, J = 13.0 Hz, 1H), 1.91-2.10 (m, 2H), 2.45 (t, J = 13.4 Hz,1H), 2.90 (t, J = 13.0 Hz, 1H), 3.68 (d, J = 6.5 Hz, 2H), 3.83 (t, J =13.9 Hz, 1H), 4.59 (t, J = 11.5 Hz, 1H), 4.94 (br s, 1H), 5.35 (q, J =6.6 Hz, 1H), 7.06 (d, J = 7.6 Hz, 1H), 7.21-7.40 (m, 5H), 7.42-7.56 (m,3H), 8.16 (d, J = 17.3 Hz, 1H). 1512

4-((R)-1-hydroxy-2-((S)-5H- imidazo[5,1-a]isoindol-5-yl)ethyl)-N-(4-(trifluoromethyl)phenyl) piperidine-1-carboxamide 78 ¹H NMR1.15-1.16 (m, 6H), 1.86 (d, 1H, J = 12.8 Hz), 2.17-2.22 (t, 1H, J = 11.2Hz), 2.66-2.75 (m, 2H), 3.68-3.76 (m, 1H), 4.04-4.08 (m, 2H), 4.60 (br,2H), 5.47 (d, 1H, J = 8.8 Hz), 6.86-6.90 (t, 1H, J = 11.2 Hz), 6.94 (s,1H), 7.09-7.31 (m, 7H), 7.45 (d, 1H, J = 7.2 Hz), 8.24 (s, 1H) 1513

(4-((R)-1-hydroxy-2-((S)-5H- imidazo[5,1-a]isoindol-5-yl)ethyl)piperidin-1-yl)(1H- imidazol-1-yl)methanone 50 ¹H NMR 1.44-1.54(m, 2H), 1.65-1.68 (m, 1H), 1.73 (d, 1H, J = 12.8 Hz), 1.98 (d, 1H, J =13.0 Hz), 2.05-2.14 (m, 1H), 2.18-2.25 (m, 1H), 2.99 (t, 2H, J = 12.0Hz), 3.82-3.87 (m, 1H), 4.16 (t, 2H, J = 10.7 Hz), 4.80 (br s, 1H), 5.41(t, 1H, J = 5.9 Hz), 7.07 (s, 1H), 7.14 (s, 1H), 7.18 (s, 1H), 7.24-7.28(m, 1H, merged with chloroform), 7.38 (t, 1H, J = 7.5 Hz), 7.43 (d, 1H,J = 7.6 Hz), 7.55 (d, 1H, J = 7.6 Hz), 7.84 (s, 1H), 7.86 (s, 1H).

Example 311-(1-(benzylsulfonyl)piperidin-4-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethanol

To a vial 2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(piperidin-4-yl)ethanoldihydrochloride (0.12 g, 0.34 mmol) in CH₂Cl₂ (3 mL) was added ethyldiisopropylamine (0.35 mL, 2.0 mmol) and benzyl sulfonyl chloride (67mg, 0.35 mmol). The reaction mixture was stirred at RT for 18 h andconcentrated. The residue was dissolved in dichloromethane (30 mL) andwashed with water (3×10 ml). The organic layer was dried over Na₂SO₄ andconcentrated. The crude product was purified by flash columnchromatography to afford 1442 as white solid (85 mg, 58%). ¹H NMR (amixture of diastereomers) 1.21-1.29 (m, 2H), 1.34-1.36 (m, 1H),1.57-1.60 (m, 1H), 1.79-1.90 (m, 2H), 2.03-2.10 (m, 1H), 2.52-2.66 (m,2H), 3.55-3.63 (m, 2H), 3.67-3.71 (m, 1H), 4.38 (s, 2H), 5.03 and 5.14(two d, 1H, J=6.0 Hz, OH), 5.39 (t, 1H, J=6.8 Hz), 7.13 and 7.16 (two s,1H), 7.29 (t, 1H, J=7.2 Hz), 7.37-7.42 (m, 6H), 7.60 (dd, 2H, J=7.8,14.2 Hz), 7.92 and 7.95 (two s, 1H).

Example 32 2-(5H-imidazo[5,1-a]isoindol-5-yl)acetic acid

To a solution of 1256 (0.41 mmol) in tetrahydrofuran (2 mL) at rt wasadded LiOH*H₂O (0.45 mmol) and water (0.5 mL) the solution was stirredovernight. The solvent was distilled off and the crude was dissolved inmethanol (1.5 mL) followed by the addition of ethyl acetate (2.5 mL),the precipitated white solid was filtered, washed with ethylacetate anddried under reduced pressure to afford 1258 (68 mg, 75%). ¹H NMR: 2.10(dd, 1H, J=18.0 Hz, 9.0 Hz), 2.66 (dd, 1H, J=15.0 Hz, 3.0 Hz), 5.43-5.47(m, 1H), 7.05 (s, 1H), 7.20 (t, 1H, J=9.0 Hz), 7.32 (t, 1H, J=9.0 Hz),7.50-7.54 (m, 2H), 7.90 (s, 1H).

Example 33 2-(5H-imidazo[5,1-a]isoindol-5-yl)ethanol

To a solution of 1256 (3.51 mmol) in a 1:2 mixture of THF:EtOH (24 mL)at rt, was added NaBH₄ (12.28 mmol) and LiCl (12.28 mmol). Afterstirring overnight, the solvents were distilled off and the crude wasdiluted with satd. NH₄Cl (20 mL). The aqueous layer was extracted withCH₂Cl₂ (3×40 mL). The combined organic extracts were dried over MgSO₄and the solvent distilled off under reduced pressure to afford a cruderesidue. The crude product was purified by silica flash chromatographyto afford 1254 (638 mg, 91%). ¹H NMR: 2.04-2.08 (m, 1H), 2.36-2.40 (m,1H), 3.84 (t, 2H, J=6.3 Hz), 5.37-5.41 (m, 1H), 7.17 (s, 1H), 7.25-7.28(m, 1H), 7.35 (d, 1H, J=6.90 Hz), 7.38 (d, 1H, J=7.2 Hz), 7.54 (d, 1H,J=7.5 Hz), 7.76 (s, 1H).

Example 34 2-(5H-imidazo[5,1-a]isoindol-5-yl)-N-methylacetamide

To a solution of 1256 (0.124 mmol) in tetrahydrofuran (1.5 mL) at rt,was added the methylamine solution (1.24 mmol, 0.62 mL, 2M in THF) andthe solution was stirred at 60° C. overnight. After cooling to rt thesolvent was distilled off under reduced pressure and the crude waspurified by column chromatography to afford 1259 (21 mg, 75%). ¹H NMR:2.43 (dd, 1H, J=20.0 Hz, 12.8 Hz), 2.91 (d, 3H, J=4.8 Hz), 2.94 (dd, 1H,J=20.0 Hz, 6.0 Hz) 5.69 (dd, 1H, J=12.8 Hz, 5.60 Hz), 5.81 (br s, 1H),7.13 (s, 1H), 7.22-7.26 (m, 1H), 7.33 (d, 1H, J=8.4 Hz), 7.38 (d, 1H,J=7.2 Hz), 7.53 (d, 1H, J=7.80 Hz), 7.67 (s, 1H).

Example 35 2-(SH-imidazo[5,1-a]isoindol-5-yl)acetaldehyde

To a solution of 1254 (0.5 mmol) in dichloromethane (5 mL) at 0° C. wasadded pyridinium chlorochromate (0.6 mmol) and the solution was allowedto warm to rt. After stirring for 4 h, the solvent was distilled offunder reduced pressure and the crude was purified by columnchromatography to afford 74 (63 mg, 64%). ¹H NMR: 2.99 (dd, 1H, J=7.5Hz, 6.0 Hz), 3.28 (dd, 1H, J=12.0 Hz), 5.61-5.65 (m, 1H), 7.18 (s, 1H),7.26-7.30 (m, 1H), 7.32 (d, 1H, J=6.0 Hz), 7.39 (t, 1H, J=6.0 Hz), 7.55(d, 1H, J=6.0 Hz), 7.68 (s, 1H), 9.80 (s, 1H).

Example 36 (E)-5-(2-bromostyryl)-5H-imidazo[5,1-a]isoindole

To a solution of 74 (1.21 mmol) in tetrahydrofuran (4 mL) at −20° C. wasadded iPrMgCl.LiCl (1.21 mmol, 1.3 M in THF) dropwise. After stirringfor 1 h at −20° C., 2-(5H-imidazo[5,1-a]isoindol-5-yl)acetaldehyde wasadded as a solution in tetrahydrofuran (2 mL) and the reaction wasallowed to warm to −10° C. After stirring for 2 h at −10° C. thereaction was quenched by adding sat'd NH₄Cl solution (2 mL) and water (2mL). The aqueous layer was extracted with EtOAc (3×15 mL). The combinedorganic extract was dried over Na₂SO₄ and concentrated under reducedpressure to afford the crude reside. Chromatographic purification of thecrude using EtOAc:MeOH (98:2) afforded 1273 (42 mg, 21%). ¹H NMR 5.77(d, 1H, J=6.0 Hz), 6.26 (dd, 1H, J=15.0 Hz, Hz, 6.0 Hz), 6.97 (d, 1H,J=15.0 Hz), 7.13-7.17 (m, 2H), 7.26-7.33 (m, 2H), 7.47-7.65 (m, 5H).

Example 37 2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl2-(((1R,2R,5S)-2-isopropyl-5-methylcyclohexyl)oxy)acetate

To a solution of 1254 (110 mg, 0.55 mmol) in CH₂Cl₂ at 0° C. was addeddiisopropylethylamine (110 mg, 0.824 mmol). The mixture was allowed tostir for 5 min and2-(((1S,2S,5R)-2-isopropyl-5-methylcyclohexyl)oxy)acetyl chloride (129mg, 0.55 mmol) was added. The solution was allowed to warm to rt andstirred for 4 h. The reaction mixture was diluted with water (10 mL) andthe organic layer was collected. The aqueous layer was extracted withCH₂Cl₂ (3×15 mL). The combined organic extract was dried (MgSO₄) andconcentrated under reduced pressure to afford the crude product. Thecrude residue was purified by flash chromatography to afford 1288 (200mg, 92%). ¹H NMR: 0.77 (d, 3H, J=3.0 Hz), 0.75-1.25 (m, 7H) 1.23-1.31(m, 2H), 1.54-1.72 (m, 3H), 1.98-2.03 (m, 1H), 2.20-2.28 (m, 2H),2.50-2.54 (m, 1H), 3.09-3.14 (m, 1H), 3.97-4.15 (m, 2H), 4.27 (t, 2H,J=4.5 Hz), 5.26-5.31 (m, 1H), 7.19 (s, 1H), 7.26-7.30 (m, 1H), 7.35 (d,1H, J=6.0 Hz), 7.39 (d, 1H, J=6.0 Hz), 7.55 (d, 1H, J=6.0 Hz), 7.75 (s,1H).

Example 38 1-Cyclohexyl-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethanamine and(E)-5-(2-Cyclohexylvinyl)-5H-imidazo[5,1-a]isoindole

To a solution of triphenylphosphine (255 mg, 0.97 mmol) in THF (10 mL)at 0° C. was added phthalimide (143 mg, 0.97 mmol) and 1304 (250 mg,0.885 mmol) followed by the dropwise addition of DEAD (0.44 mL, 0.97mmol). The reaction mixture was allowed to warm to room temperature andstirred overnight. The solvent was distilled off under reduced pressure,diluted with CH₂Cl₂ (30 mL) and washed successively with 10% aq NaOH(2×15 mL), water and brine. The organic layer was dried (Na₂SO₄) and thesolvent was evaporated under reduced pressure to afford an off-whitesolid. The solid was dissolved in EtOH (5 mL) and hydrazine monohydrate(0.09 mL, 1.77 mmol) was added. The mixture was heated at 80° C.overnight. The solution was cooled to rt and the solvent was distilledoff under reduced pressure. The crude was diluted with CH₂Cl₂ (20 mL)and the organic phase was washed with water (10 mL). The organic layerwas dried (Na₂SO₄) and the solvent was evaporated under reduced pressureto afford a crude residue that was purified by column chromatography toafford 1388 as a white solid (50 mg, 14%) and an eliminated side product1412 (30 mg). 1388 ¹H NMR: 0.97-1.24 (m, 7H), 1.62-1.71 (m, 6H), 2.0 (m,1H), 2.89 (m, 1H), 5.34 (dd, 1H, J=8.4 Hz, 15.6 Hz), 5.38 and 5.49 (twom, 1H), 7.15 (s, 1H), 7.24 (m, 1H), 7.31-7.52 (m, 3H), 7.77 and 7.81(two s, 1H). 1412 ¹H NMR: 1.11-1.28 (m, 5H), 1.55-1.75 (m, 5H),2.01-2.11 (m, 1H), 5.47 (d, 1H, J=8.0 Hz), 6.01 (dd, 1H, J=6.8 Hz, 15.0Hz), 7.18 (s, 1H), 7.26 (m, 2H), 7.36 (m, 1H), 7.52 (d, 1H, J=7.6 Hz),7.64 (s, 1H).

Example 394-(2-(6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-1-hydroxyethyl)cyclohexanone

To a solution of 1378 (186 mg, 0.52 mmol) in THF (5 mL) was added 2M HCl(5 mL) and the solution was stirred at room temperature overnight. Thesolvent was removed in vacuo and remaining solution basified with 2Maqueous NaOH (6 mL) to pH>8.0. The aqueous solution was extracted withdichloromethane (2×50 mL) and the combined organic layers were dried(Na₂SO₄) and concentrated in vacuo to give 1379 as a white solid (155mg, 95%).

¹H NMR: (CD₃OD) 1.23-2.51 (m, 11H), 3.53-3.77 (m, 2H), 5.60-5.75 (m,1H), 7.03-7.08 (m, 1H), 7.26-7.27 (m, 1H), 7.43-7.44 (m, 1H), 8.13 and8.21 (two s, 1H).

Example 401-(4-(Hydroxymethyl)cyclohexyl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)etanol(1383)

To a solution of 1386 (121 mg, 0.41 mmol) in dry THF (10 mL) at 0° C.was added BH₃.SMe₂ (0.05 mL, 0.53 mmol). The reaction mixture wasallowed to warm to room temperature and stirred overnight under anatmosphere of N₂. The solution was diluted with water (10 mL) and cooledto 0° C. 3M NaOH (0.55 mL, 1.64 mmol) and 30% (w/w) hydrogen peroxidesolution (0.19 mL, 1.64 mmol) were added sequentially. The reactionmixture was allowed to stir overnight at room temperatura. The aqueouslayer was extracted with CH₂Cl₂ (3×40 mL). The combined organic layerswere (Na₂SO₄) and concentrated under reduced pressure. The crude residuewas purified by flash column chromatography to afford 1383 as a whitesolid (45 mg, 35%). ¹H NMR MeOH-d₄: 1.20-1.78 (m, 11H), 2.02-2.22 (m,2H), 3.46-3.51 (m, 2H), 3.78-3.88 (m, 2H), 5.38-5.44 (m, 1H), 7.12 and7.14 (two s, 1H), 7.27-7.46 (m, 2H), 7.52-7.61 (m, 2H), 7.92 and 7.95(two s, 1H).

Example 41 1-(5H-imidazo[5,1-a]isoindol-5-yl)-2-methylpropan-2-ol

To a stirred solution of 1256 (48 mg, 0.20 mmol) in THF at 0° C. wasadded MeMgBr 1.0 M in THF (0.4 mL,) dropwise. The resulting solution wasallowed to stir at rt for 2 h. The reaction was quenched by the carefuladdition of methanol to the reaction mixture. The crude mixture wasconcentrated, absorbed in silica gel and purified by columnchromatography to afford 1335 (24 mg, 52%). ¹H NMR 1.43 (s, 3H), 1.49(s, 3H), 2.05-2.30 (m, 2H), 5.30-5.35 (m, 1H), 7.14 (s, 1H), 7.20-7.40(m, 3H), 7.52 (d, 1H, J=9.6 Hz), 8.02 (s, 1H).

Example 424-(2-(6-Fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-1-hydroxyethyl)cyclohexanol

To a mixture of 1379 (38 mg, 0.12 mmol) in anhydrous MeOH at 0° C., wasadded NaBH₄ (0.36 mmol) and the solution was allowed to stir for 2 h atrt. The solvent was distilled off under reduced pressure and the residuewas partitioned between CH₂Cl₂ (15 mL) and satd. NH₄Cl (5 mL). Theorganic layer was collected and the aqueous layer was extracted withCH₂Cl₂ (2×10 mL). The combined organic extract was washed with brine,dried (Na₂SO₄) and the solvent evaporated. The crude was purified bycolumn chromatography (25% MeOH in EtOAc) to afford 1371 (29 mg, 76%).¹H NMR MeOH-d₄ (mixture of diastereomers): 1.00-1.40 (m, 5H), 1.40-2.10(m, 5H), 2.37-2.47 (m, 1H), 3.39-3.57 (m, 2H), 5.54 and 5.72 (two m,1H), 6.98-7.06 (m, 1H), 7.15-7.18 (m, 1H), 7.37-7.42 (m, 2H), 7.93-7.99(m, 1H).

Example 43 1-cyclohexyl-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethanone oxime

To a solution of 86 (160 mg, 0.57 mmol) in EtOH (3 mL) at rt was added50% aq NH₂OH (1.71 mmol) and the solution was stirred at 50° C.overnight. After cooling to rt, the solvent was removed under reducedpressure and the crude was purified by flash column chromatography toafford 1360 (120 mg, 71%). ¹H NMR 0.99-1.15 (m, 5H), 1.45-1.72 (m, 6 H),2.43 and 2.58 (two m, 1H), 2.70 and 2.91 (m, 1H), 4.69 (m, 1H),7.23-7.29 (m, 3H), 7.40 and 7.46 (two m, 1H), 7.53 and 7.58 (two m, 1H),7.75 and 7.76 (two s, 1H), 10.34 and 10.41 (two s, 1H).

Example 44 1-cyclohexyl-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethanamine

To a solution of 1360 (100 mg, 0.34 mmol) in 1:1 EtOH/AcOH (4 mL) wasadded zinc powder (67 mg, 1.0 mmol) and the mixture was stirredovernight at it. The solvent was removed under reduced pressure and themixture was suspended in 1:1 MeOH/DCM (10 mL) and filtered. The filtratewas collected and concentrated under reduced pressure. The crude waspurified by ion-exchange chromatography using water and NH₄OH as theeluent to afford 1364 (25 mg, 26%). ¹H NMR (mixture of diastereomers)0.89-1.75 (m, 11H), 2.24 and 2.42 (two m, 1H), 2.62 (m, 1H), 4.52 (m,1H), 7.09 (t, 1H, J=9.2 Hz), 7.29 (m, 2H), 7.38 (m, 1H), 7.47 (m, 1H),7.60 (d, 1H, J=9.2 Hz).

Example 45 General Procedure for the Removal the BOC Protecting Groupfrom Substituted Anilines and Amines

To a solution of 17, 1300, 1328 or 1363 (66.0 μmol) in dichloromethane(2 mL) was added trifluoroacetic acid (0.2 mL, 2.66 mmol) and themixture was stirred at it for 2 h. The solvents were distilled off underreduced pressure and the solution was basified with satd. NaHCO₃. Theaqueous layer was extracted with EtOAc (3×15 mL). The combined organiclayers were washed with water, brine and dried (Na₂SO₄). The solution asfiltered and the solvent removed under reduced pressure. The cruderesidue was purified by column chromatography to afford the followingcompounds.

# Compound Name Yield (%) 1330

1-(2-aminophenyl)-2-(5H- imidazo[5,1-a]isoindol-5- yl)ethanone 76 ¹H NMR3.40 (dd, 1H, J = 18.0 Hz, 9.6 Hz), 3.70 (dd, 1H, J = 18.0 Hz, 3.3 Hz),5.81 (dd, 1H, J = 6.3 Hz, J = 3.3 Hz), 6.43 (br s, 2H), 6.60 (t, 1H, J =7.5 Hz), 6.68 (d, 1H, J = 8.4 Hz), 7.18 (s, 1H), 7.29 (m, 2H), 7.36 (d,2H, J = 7.8 Hz), 7.55 (d, 2H, J = 7.5 Hz), 7.74 (s, 1H) 1370

2-(5H-imidazo[5,1-a]isoindol-5- yl)-1-(piperidin-4-yl)ethanol 15 ¹H NMR(Mixture of diastereomers) 1.66-1.87 (m, 6 H), 2.20 (s, 1H), 2.75 (m,2H), 3.40 (m, 2H), 3.84 (m, 2H), 5.27 and 5.34 (two m, 1H), 7.05 (s,1H), 7.19 (t, 1H, J = 4.0 Hz), 7.30 (t, 1H, J = 8.0 Hz), 7.38 (d, 1H, J= 8.0 Hz), 7.46 (d, 1H, J = 8.0 Hz), 8.06 and 8.12 (two s, 1H) 1301

1-(4-aminophenyl)-2-(5H- imidazo[5,1-a]isoindol-5- yl)ethanone 87 ¹H NMR3.35 (dd, 1H, J = 18.6 Hz, 9.6 Hz), 3.61 (dd, 1H, J = 18.6 Hz, 9.6 Hz),4.13 (br s, 2H), 5.84 (dd, 1H, J = 18.6 Hz, 9.6 Hz), 6.65 (d, 2H, J =8.7 Hz), 7.18 (s, 1H), 7.24-7.29 (m, 1H), 7.37-7.58 (m, 3H), 7.74-7.82(m, 3H) 1369

1-(3-aminophenyl)-2-(5H- imidazo[5,1-a]isoindol-5- yl)ethanol 58(MeOH-d₄) 2.32 (t, 2H, J = 6.3 Hz), 4.89-4.94 (m, 1H), 5.30 and 5.38(two m, 1H), 6.64 (d, 1H, J =7.8 Hz), 6.71-6.77 (m, 2H), 7.05-7.10 (m,1H), 7.28-7.41 (m, 2H), 7.51-7.58 (m, 2H), 7.66 (s, 1H)

Example 465-(2-Cyclohexyl-2-hydroxyethyl)-5H-imidazo[5,1-a]isoindol-9-ol

To a solution of 1372 (28 mg, 0.09 mmol) in DCM (3 mL) at 0° C. wasadded BBr₃ (1 M in DCM, 0.27 mL, 0.27 mmol) dropwise and the mixture wasallowed to stir at 0° C. for 2 h. Saturated aqueous NaHCO₃ was added andthe aqueous layer was extracted with DCM (2×10 mL). The combined organiclayers were dried (Na₂SO₄) and concentrated under reduced pressure. Theresidue was purified by flash column chromatography to afford 1373 (15mg, 56%). ¹H NMR MeOH-d₄: (mixture of diastereomers) 1.04-1.12 (m, 1H),1.15-1.33 (m, 4H), 1.62-1.86 (m, 5H), 2.00-2.07 (m, 1H), 3.55 and 3.70(two m, 1H), 5.38 and 5.44 (two m, 1H), 6.80 and 6.81 (two d, 1H, J=8.0Hz), 6.90 and 6.99 (two d, 1H, J=7.6 Hz), 7.03 and 7.05 (two s, 1H),7.12-7.16 (m, 1H), 7.93 and 7.99 (two s, 1H).

Example 47 3-Cyclohexyl-3-hydroxy-1-(2-iodophenyl)propan-1-one

To a solution of diisopropylamine (1.6 mL, 11.1 mmol) in THF (38 mL) at0° C. was added n-BuLi (4.1 mL, 10.2 mmol) under an atmosphere of N₂.After 30 min the solution was cooled to −30° C. and a solution of1-(2-iodophenyl)ethanone (2.27 g, 9.23 mmol) in THF (6 mL) was addeddropwise to the mixture and was stirred for 45 min at −30° C. Themixture was cooled to −78° C. and cyclohexylcarboxaldehyde (1.2 mL, 9.69mmol) was added dropwise and the mixture was allowed to warm to −40° C.over 2 h. The reaction was quenched by the addition of saturated aqueousNH₄Cl. The aqueous layer was extracted with EtOAc (2×50 mL). Thecombined organic layers were washed with brine, dried (Na₂SO₄), filteredand concentrated. The residue was purified by flash columnchromatography to afford the title compound as yellow oil (2.56 g, 78%).¹H NMR: 1.02-1.27 (m, 4H), 1.41-1.49 (m, 1H), 1.66-1.76 (m, 4H), 1.89(d, 1H, J=12.4 Hz), 2.88 (d, 1H, J=3.2 Hz), 2.98 (dd, 1H, J=9.2 Hz, 17.2Hz), 3.13 (dd, 1H, J=2.0 Hz, 17.2 Hz), 3.99-4.01 (m, 1H), 7.11-7.15 (m,1H), 7.42 (d, 2H, J=4.4 Hz), 7.93 (d, 1H, J=8.0 Hz).

Example 483-(tert-Butyldimethylsilyloxy)-3-cyclohexyl-1-(2-iodophenyl)propan-1-one

To a solution of 3-Cyclohexyl-3-hydroxy-1-(2-iodophenyl)propan-1-one(2.56 g, 7.15 mmol) and DMAP (1.05 g, 8.58 mmol) in DMF (40 mL) wasadded TBSCl (1.62, 10.7). The reaction mixture was stirred at rt for 18h and poured into water (40 mL). The aqueous layer was extracted withEtOAc (2×50 mL) and the combined organic layers were washed with water(2×20 mL), brine (10 mL), dried (Na₂SO₄), filtered and concentrated. Thecrude was purified by flash column chromatography to afford 106 as clearoil (3.15 g, 93%). ¹H NMR: 0.01 (s, 3H), 0.08 (s, 3H), 0.86 (s, 9H),1.12-1.24 (m, 6H), 1.43-1.52 (dt, 1H, J=3.6 Hz, 15.2 Hz), 1.65-1.76 (m,4H), 2.91 (dd, 1H, J=6.8 Hz, 22.0 Hz), 3.1 (dd, 1H, J=9.4 Hz, 22.0 Hz),4.19-4.24 (m, 1H), 7.11 (dt, 1H, J=2.4 Hz, 10.0 Hz), 7.40 (t, 1H, J=9.6Hz), 7.48 (dd, 1H, J=2.4 Hz, 10.4 Hz), 7.92 (d, 1H, J=10.4 Hz).

Example 49(1R,3R)-3-(tert-Butyldimethylsilyloxy)-3-cyclohexyl-1-(2-iodophenyl)propan-1-oland(1R,3S)-3-(tert-butyldimethylsilyloxy)-3-cyclohexyl-1-(2-iodophenyl)propan-1-ol

A mixture of 106 (3.15 g, 6.67 mmol), BH₃.SMe₂ (0.63 mL, 6.67 mmol) andS-2-methyl-CBS-oxazaborolidine (370 mg, 1.33 mmol) in THF (50 ml) wasstirred at room temperature for 16 h. Aqueous 6 M HCl (4 mL) was addedand the mixture was stirred for 5 minutes. The mixture was poured intowater (20 mL) and the aqueous layer was extracted with EtOAc (2×40 mL).The combined organic layers were washed with brine (20 mL), dried(Na₂SO₄), filtered and concentrated. The residue was purified by flashcolumn chromatography (3%-6% EtOAc/hexanes gradient). The twodiastereomers 107 and 108 were separated in this manner. Thestereochemistry was confirmed by developing 107 and 108 on a normalphase analytical silica gel TLC plate against an authentic sample of108. An authentic sample of 108 was prepared independently by anenantioselective aldol reaction as outlined in Scheme 4. ¹H NMR:(1R,3S): 0.15 (s, 3H), 0.18 (s, 3H), 0.87 (s, 9H), 1.08-1.27 (m, 5H),1.52-1.68 (m, 4H), 1.75-1.89 (m, 4H), 4.02-4.10 (m, 1H), 4.91 (d, 1H,J=9.6 Hz), 6.95 (t, 1H, J=6.8 Hz), 7.37 (t, 1H, J=7.4 Hz), 7.61 (d, 1H,J=6.8 Hz), 7.78 (d, 1H, J=7.2 Hz). ¹H NMR: (1R,3R): 0.12 (s, 3H), 0.16(s, 3H), 0.88-0.93 (m, 2H), 0.97 (s, 9H), 1.12-1.17 (m, 1H), 1.27-1.31(m, 2H), 1.57-1.79 (m, 5H), 1.91-2.07 (m, 3H), 3.70-3.72 (m, 1H), 4.19(s, 1H), 5.20 (d, 1H, J=10.4 Hz), 6.94 (t, 1H, J=6.8 Hz), 7.38 (t, 1H,J=7.4 Hz), 7.60 (d, 1H, J=7.2 Hz), 7.77 (d, 1H, J=7.2 Hz).

Example 50(1R,3S)-3-(tert-Butyldimethylsilyloxy)-3-cyclohexyl-1-(2-iodophenyl)propyl-4-methylbenzenesulfonate

To a solution of 107 or 108 (300 mg, 0.63 mmol) in dichloromethane (5mL) was added triethylamine (0.18 mL, 1.26 mmol) and DMAP (85 mg, 0.70mmol. The reaction mixture was stirred at room temperature for 5 min andp-toluenesulfonyl chloride (145 mg, 0.76 mmol) was added. The reactionmixture was refluxed for 18 h. The solvent was removed under reducedpressure. The residue was dissolved in EtOAc (30 ml) and the organiclayer was washed with water (10 ml), satd aq NaHCO₃ (15 mL) and brine.The organic layer was dried (Na₂SO₄), filtered and concentrated. Thetitle compound was used in the next step without further purification.

Example 51(1R,3R)-3-(tert-Butyldimethylsilyloxy)-3-cyclohexyl-1-(2-iodophenyl)propyl-4-methylbenzenesulfonate

(1R,3R)-3-(tert-Butyldimethylsilyloxy)-3-cyclohexyl-1-(2-iodophenyl)propyl-4-methylbenzenesulfonatewas prepared as described in the above procedure. The title compound wasused in the next step without further purification.

Example 521-((1S,3S)-3-(tert-Butyldimethylsilyloxy)-3-cyclohexyl-1-(2-iodophenyl)propyl)-1H-imidazole

To a suspension of NaH (55 mg, 2.17 mmol) in dry DMF (4 mL) was addedimidazole (148 mg, 2.17 mmol). The solution was stirred for 2 h and asolution of(1R,3S)-3-(tert-butyldimethylsilyloxy)-3-cyclohexyl-1-(2-iodophenyl)propyl4-methylbenzenesulfonate (341 mg, 0.54 mmol) in DMF (2 mL) was added.The reaction mixture was heated at 60° C. for 14 h. The reaction mixturewas poured into water (10 mL) and the aqueous layer was extracted withEtOAc (2×20 mL). The combined organic layers were washed with water(2×10 mL), brine (10 mL), dried (Na₂SO₄), filtered and concentrated. Theresidue was purified by flash column chromatography to afford 109 asclear gel (130 mg, 46%). ¹H NMR: (1S, 3S) 0.03 (s, 3H), 0.05 (s, 3H),0.97 (s, 9H), 1.11-1.31 (m, 5H), 1.53-1.59 (m, 2H), 1.68-1.79 (m, 4H),2.20-2.23 (m, 2H), 3.59-3.62 (m, 1H), 5.75-5.79 (m, 1H), 7.01-7.13 (m,3H), 7.17 (s, 1H), 7.34-7.37 (m, 1H), 7.73 (s, 1H), 7.93 (d, 1H, J=7.8Hz).

Example 531-((1S,3R)-3-(tert-Butyldimethylsilyloxy)-3-cyclohexyl-1-(2-iodophenyl)propyl)-1H-imidazole(78)

Compound III was prepared as described for compound 109 in the aboveprocedure. 111 was isolated as a clear gel (42% over two steps). ¹H NMR:(1S,3R) 0.05 (s, 3H), 0.07 (s, 3H), 0.97 (s, 9H), 1.12-1.29 (m, 5H),1.47-1.50 (m, 1H), 1.69-1.77 (m, 3H), 1.82-1.85 (m, 2H), 2.20-2.28 (m,1H), 2.39-2.47 (m, 1H), 3.56-3.60 (m, 1H), 5.63 (t, 1H, J=7.4 Hz),6.97-6.98 (m, 1H), 7.04-7.11 (m, 2H), 7.31-7.34 (m, 2H), 7.45 (dt, 1H,J=1.0 Hz, 7.6 Hz), 7.64 (s, 1H), 7.96 (dd, 1H, J=1.2 Hz, 8.0 Hz).

Example 54(S)-5-((S)-2-(tert-Butyldimethylsilyloxy)-2-cyclohexylethyl)-5H-imidazo[5,1-a]isoindole

To a vial containing 109 (65 mg, 0.12 mmol) was addeddicyclohexylmethylamine (0.04 mL, 0.19 mmol), PPh₃ (13 mg, 0.05 mmol)and DMF (4 mL). The mixture was degassed for 10 min and Pd(OAc)₂ (6 mg,25 mol) was added. The mixture was heated at 95° C. for 5 h. Aftercooling to rt, the mixture was diluted with ethyl acetate (15 mL) andpassed through a Celite pad. The filter cake was washed with ethylacetate. The organic layer was washed with water (3×10 mL), brine (10mL), dried (Na₂SO₄), filtered and concentrated. The crude residue wasused directly in the next step.

Example 55(S)-5-((R)-2-((tert-butyldimethylsilyl)oxy)-2-cyclohexylethyl)-5H-imidazo[5,1-a]isoindole

Compound 111a was prepared as described in the above procedure. Thecrude residue was used directly in the next step.

Example 56(S)-1-cyclohexyl-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)ethanol (1417)

To a vial containing crude 109a (60 mg, 0.15 mmol) was added 1% HCl inethanol (2 mL). The reaction mixture was heated at 50° C. for 3 h andpoured into saturated aqueous NaHCO₃ (5 mL). The aqueous layer wasextracted with dichloromethane (2×15 mL). The combined organic layerswere dried (Na₂SO₄), filtered and concentrated. The residue was purifiedby flash column chromatography to afford 1417 as a white solid (17 mg,47% over 2 steps). ¹H NMR: (1S,2S) 1.02-1.28 (m, 5H), 1.40-1.42 (m, 1H),1.67-1.83 (m, 4H), 1.91 (d, 1H, J=12.4 Hz), 2.22-2.30 (m, 1H), 2.82 (brs, 1H), 3.80-3.83 (m, 1H), 5.52 (dd, 1H, J=3.0 Hz, 10.8 Hz), 7.20 (s,1H), 7.25-7.29 (m, 1H), 7.36-7.40 (m, 2H), 7.56 (d, 1H, J=7.6 Hz), 7.84(s, 1H). Absolute configuration of this diasteromer was confirmed byX-ray crystallography of HBr:1417 salt crystals (FIG. 1).

Example 57(R)-1-cyclohexyl-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)ethanol (1418)

Compound 1418 was prepared as described for compound 111a in the aboveprocedure. 1418 was isolated as a colorless solid (42% over 2 steps). ¹HNMR: (1S,2R) 0.97-1.26 (m, 5H), 1.32-1.39 (m, 1H), 1.63-1.67 (m, 2H),1.71-1.80 (m, 3H), 2.00-2.06 (m, 1H), 2.10-2.18 (m, 1H), 2.55 (br s,1H), 3.70-3.74 (m, 1H), 5.35 (t, 1H, J=7.6 Hz), 7.14 (s, 1H), 7.19-7.23(m, 1H), 7.34 (t, 1H, J=7.6 Hz), 7.42 (d, 1H, J=7.4 Hz), 7.52 (d, 1H,J=7.4 Hz), 7.78 (s, 1H).

Example 58(trans)-1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)cyclohexanecarboxylicacid (1436)

To a solution of 1426 (268 mg, 0.79 mmol) in THF:Water 3:1 (4 mL) wasadded lithium hydroxide monohydrate (99 mg, 2.36 mmol). The solution wasallowed to stir for 18 h. The THF was removed under reduced pressure andthe solution was neutralized to pH=5 with 1M HCl. The solution wasconcentrated under reduced pressure and to the remaining residue wasadded 20% MeOH/DCM. The residue was filtered through a plug of silicagel and the plug was eluted with 200 mL 20% MeOH/DCM. The solution wasconcentrated to afford the NLG-1436 as a light yellow solid 193 mg(75%). ¹H NMR (DMSO-d6): 0.83-0.85 (m, 1H), 1.05-1.25 (m, 4H), 1.41-1.45(m, 2H), 1.85-1.88 (m, 3H), 2.03-2.21 (m, 2H), 3.61-3.64 (m, 1H),5.35-5.42 (m, 1H), 7.11 and 7.13 (two s, 1H), 7.27 (t, 1H, J=7.0 Hz),7.37 (t, 1H, J=7.4 Hz), 7.49 and 7.56 (two d, 1H, J=7.5 Hz), 7.59 (d,1H, J=7.5 Hz), 7.88 and 7.92 (two s, 1H), 11.98 (br s, 1H).

Example 591-((trans)-4-(hydroxymethyl)cyclohexyl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethanol(NLG-1430)

To a solution of 1426 (100 mg, 0.30 mmol) in THF:EtOH (3 mL, 1:2 ratio)at rt, was added NaBH₄ (48.1 mg, 1.27 mmol) and LiCl (53.9 mg, 1.27mmol). The reaction mixture was stirred overnight. The solvents wereremoved under reduced pressure and the crude residue was diluted withsat'd NH₄Cl (20 mL). The product was extracted with EtOAc (3×10 mL). Thecombined organic extract was dried over Na2SO4 and the solvent wasremoved under reduced pressure. The crude product was purified by silicaflash chromatography to afford 1430 (78 mg, 85%). ¹H NMR (a mixture ofdiastereomers) 0.94-1.13 (m, 4H), 1.14-2.18 (m, 10H), 3.45 (d, J=6.3 Hz,2H), 3.73-3.78 (m, 1H), 5.30-5.38 (m, 1H), 7.17 (s, 1H), 7.22-7.27 (mmerged with CHCl₃, 1H), 7.33-7.44 (m, 2H), 7.54 (d, J=7.6 Hz, 1H), 7.83(d, J=10.4 Hz, 1H).

Example 60(trans)-1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)-N-(2-methylsulfonamido)ethyl)cyclohexanecarboxamide(1432)

To a vial containing N-(2-aminoethyl)methanesulfonamide dihydrochloride(56.4 mg, 0.27 mmol) in DMF (4 mL) was added 1436 (83 mg, 0.25 mmol),DIPEA (197 mg, 1.53 mmol) and HATU (106 mg, 0.28 mmol). The reaction wasstirred at RT for 18 h and concentrated. The residue was purified bycolumn chromatography on silica gel using hexanes/EtOAc 10%->60%gradient. The compound was isolated as a light yellow solid 72 mg (64%).¹H NMR: (CD3OD) 1.04-1.14 (m, 2H), 1.38-1.46 (m, 3H), 1.73-1.96 (m, 4H),2.11-217 (m, 2H), 2.32-2.38 (m, 1H), 2.93 and 2.97 (two s, 3H), 3.15 (t,1.7H, J=6.4 Hz), 3.29-3.31 (m overlap with, 1H), 3.54-3.58 and 3.78-3.80(two m, 1H), 5.57-5.66 (t and dd, 1H, J=6.3 and J=2.6, 9.2H), 7.33-7.47(m, 3H), 7.52 and 7.60 (two d, 1H, J=7.6 Hz), 7.68-7.71 (m, 0.8H), 7.91(s, 0.4H), 8.21 (dd, 0.6H, J=1.1, 8.4 Hz), 8.44 (s, 0.4H), 8.53-8.57 (m,1H).

Example 61(cis)-4-(2-(6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-1-hydroxyethyl)cyclohexanol

To a solution of NLG-1379 (60 mg, (0.19 mmol) in dry THF (5 mL) at −78°C. under a nitrogen atmosphere was added lithium trisiamylborohydridesolution (1.0 M in THF) (0.38 mL, 0.38 mmol). The resulting mixture wasstirred vigorously for 3 h at −78° C. and then allowed to warm to roomtemperature (1 h). The reaction mixture was quenched with 1:1 H₂O/EtOH(4 mL). The reaction was acidified with 6 N HCl followed by basificationwith sat'd K₂CO₃ solution. The aqueous layer was extracted withdichloromethane (5×15 mL). The combined organic layers were dried overNa₂SO₄, filtered and concentrated under reduced pressure to afford acrude residue. The residue was purified by column chromatography toafford 1465 35 mg (58%). Mixture of diastereomers ¹H NMR: 1.45-2.15 (m,10H), 2.35-2.51 (m, 1H), 3.66-3.79 (two m, 1H), 4.03 (br s, 1H), 5.48(t, 1H, J=5.1 Hz, isomer), 5.67 (dd, 1H, J=10.6, 2.8 Hz), 6.91-6.95 (m,1H), 7.19 (d, 1H, J=5.4 Hz), 7.25-7.39 (m, 2H), 7.88 (two, s, 1H).

The mixtures of four diastereomers (1465) were separated by preparativechiral super critical fluid chromatography (SFC) to afford the purediasteromers 1482-1485. SFC was performed on RegisPack 5 column inisopropanol/CO2: 0.2% DEA.

1482 and 1484 ¹H NMR (CD₃OD) δ 1.16 (d, J=6.1 Hz, 1H), 1.23 (d, J=17.8Hz, 2H), 1.28 (s, 1H), 1.37-1.65 (m, 6H), 1.73 (s, 2H), 1.90-2.14 (m,1H), 2.48 (d, J=15.2 Hz, 1H), 3.55 (s, 1H), 3.90 (s, 1H), 5.58 (s, 1H),6.91-7.08 (m, 1H), 7.16 (s, 1H), 7.41 (s, 2H), 7.96 (d, J=28.8 Hz, 1H).

1483 and 1485 ¹H NMR: (CD₃OD) δ 1.15 (d, J=6.4 Hz, 1H), 1.26 (d, J=24.4Hz, 2H) 1.41-1.79 (m, 8H) 2.35-2.50 (m, 1H), 3.65 (d, J=7.8 Hz, 1H),3.90 (s, 1H), 5.69 (dd, J=10.1, 2.4 Hz, 1H), 6.93-7.08 (m, 1H), 7.18 (s,1H), 7.41 (dd, J=5.2, 3.5 Hz, 2H), 7.94 (s, 1H).

Example 622-(6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-1-((trans)-4-hydroxycyclohexyl)ethanone

To a suspension of NaH (1.11 g, 46.2 mmol) in THF (150 mL) at −10° C.was added a solution of 126 (18.5 g, 50.8 mmol) in THF (75 mL) dropwiseand the mixture was stirred for 45 min at 0° C. Aldehyde 4 (20.0 g, 46.4mmol) was added as a solution in THF (120 mL) dropwise over a period of15 min. After stirring for 1 h at 0° C. the reaction mixture was allowedto warm to rt and was stirred overnight. The solvent was distilled offunder reduced pressure and the crude was diluted with sat'd NH₄Cl (80mL), water (100 mL) and EtOAc (100 mL). The solution was partitioned ina separatory funnel and the organic layer was collected. The aqueouslayer was extracted with EtOAc (3×150 mL) and the combined organicfractions were washed with brine and dried over Na₂SO₄. The solution wasfiltered and concentrated under reduced pressure to afford the crudeproduct. The crude was stirred in a mixture of acetic acid (20 mL) andMeOH (170 mL) at 90° C. for 1.5 h. After cooling to 50° C. the reactionmixture was treated with 6N HCl (20 mL) and stirred for 30 minutes.After cooling to rt the solvent was distilled off and sat'd NaHCO₃ (200mL) was added to the residue followed by CH₂Cl₂ (200 mL). The layerswere separated and the aqueous layer was extracted with CH₂Cl₂ (2×100mL). The combined organic layers were dried over Na₂SO₄ and the solventevaporated under reduced pressure to afford the crude product which waspurified by using flash silica gel column chromatography to afford 154(13.8 g, 95%).

Example 63(trans)-4-(2-(6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-1-hydroxyethyl)cyclohexanol(1475)

To a solution of 154 (13.8 g, 43.9 mmol) in MeOH (150 mL) at −10 to 0°C., was added NaBH₄ (4.98 g, 131.71 mmol) in small portions and thesolution was allowed to stir for 4 h. The solvent was distilled offunder reduced pressure and the mixture was diluted by addition ofsaturated NH₄Cl solution (200 mL) and dichloromethane (200 mL) and themixture was stirred for 25 min. The organic layer was separated and theaqueous layer was extracted with a mixture of 5% 2,2,2-trifluorethanolin CH₂Cl₂ (5×75 mL). The combined organic extract was washed with brine,dried (MgSO4) and concentrated under reduced pressure to afford thecrude. Purification by column chromatography afforded 1475 as a whitesolid (13.24 g, 95%). ¹H NMR (a mixture of diastereomers): 1.07-2.52 (m,11H), 3.48-3.68 (two m, 2H), 5.45 (t, 1H, J=6.0 Hz), 5.65 (dd, 1H,J=9.0, 3.0 Hz), 6.89-6.96 (m, 1H), 7.16 (s, 1H), 7.29-7.38 (m, 2H), 7.80and 7.88 (two s, 1H).

The mixtures of the four diasteromers were separated by preparativechiral super critical fluid chromatography to afford the purediasteromers 1486-1489. Separation by SFC was performed by a firstpassage through an AD-H column (Regis Technologies, Inc.) to separatecompounds 1487, 1486+1488 and 1489. The peak comprising a mixture of1486+1488 was separated by SFC in a Whelk-O1 column (Regis Technologies,Inc). All separations were done in isopropanol:CO2 (10:90)+DEA 0.1%.

NLG-1486 and NLG-1489 ¹H NMR: 1.03-1.26 (m, 6H), 1.43-1.47 (m, 2H),1.93-1.96 (m, 2H), 2.45-2.50 (m, 3H), 3.48 (s, 1H), 3.61 (s, 1H), 5.62(d, J=8.9 Hz, 1H), 6.91 (t, J=8.6 Hz, 1H), 7.12 (s, 1H), 7.26-7.30 (inmerged with CHCl₃, 2H), 7.79 (s, 1H).

NLG-1487 and NLG-1488 ¹H NMR: 0.95-1.33 (m, 6H), 1.61-1.64 (m, 1H),1.79-1.82 (m, 1H), 1.91-2.04 (m, 4H), 2.28 (d, J=14.4 Hz, 1H), 3.42-3.45(m, 1H), 3.62 (s, 1H), 5.37 (t, J=4.9 Hz, 1H), 6.88 (t, J=8.9 Hz), 7.05(s, 1H), 7.24-7.31 (in merged with CHCl₃, 2H), 7.84 (s, 1H).

Synthesis of ProDrugs of 1304 Example 64 Sodium1-cyclohexyl-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl phosphate (1434)

To a solution of 1304 (150 mg, 0.53 mmol) and pyridine (85.7 μL, 1.1mmol) in dichloromethane (4 mL) at 0° C. was added POCl₃ (99.3 μL, 1.06mmol) and the solution was allowed to warm to rt. After stirringovernight the reaction was quenched with NaHCO3 sat'd (5 mL), andstirred for 15 minutes. The solvents were evaporated under reducedpressure and the solid was washed with THF (2×15 mL). The solvent wasremoved under reduced pressure to afford the crude residue. The residuewas dissolved in DCM (5 mL) and passed through a plug of Na₂SO₄ toremove water. The solvent was evaporated under reduced pressure toafford 1434.

(33%). ¹H NMR (a mixture of diastereomers): (CD₃OD) 1.15-1.41 (m, 6H),1.59-1.82 (m, 5H), 1.98-2.04 (m, 1H), 2.56-2.86 (two m, 1H), 3.57-3.58and 4.08-4.11 (two m, 1H), 5.29-5.54 (two m, 1H), 7.11 and 7.16 (two s,1H), 7.25-7.47 (m, 3H), 7.53-7.60 (m, 1H), 7.83 and 7.95 (two s, 1H).

Example 65 1-cyclohexyl-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl acetate

A solution of 1304 (80 mg, 0.28 mmol) and 4-dimethylaminopyridine (1.04mg, 8.5 μmol) in pyridine (3 ml) was treated with acetic anhydride (32μL, 0.34 mmol) at RT and the reaction was stirred overnight. Thesolution was concentrated in vacuo and the residue was dissolved indichloromethane (10 ml) and washed successively with water (3×10 ml) anddried over Na₂SO₄. The solution was concentrated and the crude waspurified by flash column chromatography to afford the desired product asyellow gel (75 mg, 82%). ¹H NMR (a mixture of diastereomers): 0.76-1.25(m, 5H), 1.30-1.75 (m, 6H), 1.78-2.20 (m, 4H), 2.26-2.40 (m, 1H),4.96-5.12 (m, 2H), 7.17-7.39 (m, 4H), 7.51-7.53 (m, 1H), 7.71 and 8.00(two s, 1H).

Example 664-(1-cyclohexyl-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethoxy)-4-oxobutanoicacid (1428)

A solution of 1304 (48 mg, 0.17 mmol) and 4-dimethylaminopyridine (0.83mg, 6.8 μmol) in dichloromethane (3 ml) was treated with succinicanhydride (19 mg, 0.19 mmol) and DIPEA (33 μL, 0.19 mmol) at RT and thereaction was stirred overnight. The solution was poured into saturatedNH₄Cl (10 mL) and extracted with dichloromethane (3×10 ml). The combinedorganic layers were dried over Na₂SO₄ and concentrated. The crudeproduct was crystallized from ethanol/chloroform (1:4) to afford 1428 aswhite solid (62 mg, 95%). ¹H NMR (a mixture of diastereomers): 0.93-1.65(m, 11H), 1.90-2.32 (m, 1H), 2.50-2.90 (m, 3H), 2.92-3.05 (m, 1H), 3.57and 3.73 (m, 1H), 5.20-5.22 (m, 1H), 5.29-5.33 (m, 1H), 6.41-6.78 (m,1H), 7.16-8.00 (m, 5H), 12.20-12.80 (br s, 1H).

Example 67 1-cyclohexyl-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl benzoate(1431)

A solution of 1304 (76 mg, 0.27 mmol) and 4-dimethylaminopyridine (1.0mg, 8.1 mol) in pyridine (3 ml) was treated with benzoic anhydride (73mg, 0.32 mmol) at RT and the reaction was stirred overnight. Thesolution was concentrated in vacuo and the residue was dissolved indichloromethane (10 ml) and washed successively with saturated NaHCO₃(10 mL), water (10 ml) and dried over Na₂SO₄. The solution wasconcentrated and the crude was purified by flash column chromatographyto afford 1431 (25 mg, 23%). ¹H NMR (a mixture of diastereomers):0.88-1.25 (m, 7H), 1.62-1.90 (m, 4H), 2.15-2.25 (m, 1H), 2.49-2.58 (m,1H), 5.19-5.21 (m, 1H), 5.34-5.37 (m, 1H), 7.16-7.28 (m, 4H), 7.40-7.64(m, 4H), 7.80 (s, 1H), 8.00-8.02 (d, J=6.3 Hz, 1H), 8.12-8.14 (d, J=5.7Hz, 1H).

Example 68 1-cyclohexyl-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethylphenylcarbamate (1427)

To a solution of 1304 (40 mg, 0.14 mmol) in THF (5 mL) was addedtriethylamine (43 μL, 0.31 mmol) followed by phenylisocyanate (17 μL,0.16 mmol). The reaction mixture was stirred at RT for 18 h andconcentrated. The crude product was purified using flash columnchromatography (4:1 EtOAc:MeOH) to afford 1427 as colorless gel (19 mg,34%). ¹H NMR (a mixture of diastereomers): 1.02-1.04 (m, 5H), 1.56-1.70(m, 6H), 2.10-2.14 (m; 1H), 2.31-2.40 (m, 1H), 5.02-5.10 (m, 1H),5.18-5.24 (m, 1H), 7.04-7.08 (m, 1H), 7.18-7.35 (m, 6H), 7.39-7.41 (m,2H), 7.50 (d, J=4 Hz, 1H), 7.65 (d, J=8 Hz, 1H), 7.74 (s, 1H).

Example 69 General Procedure for the Synthesis of Prodrugs of 1304

To a vial containing 1304 (0.5 mmol) in dichloromethane (5 mL) was addedthe appropriate carboxylic acid (1.1 mmol), diisopropylethyl amine (3.0mmol) and HATU (1.3 mmol). The reaction mixture was stirred at rt for 48h and poured into saturated aqueous NaHCO₃ (10 mL) and the aqueous layerwas extracted with dichloromethane (2×20 mL). The combined organiclayers were dried over Na₂SO₄, and concentrated. The crude product wasdissolved in dichloromethane (6 mL) and TFA (2 mL) was added. Thereaction mixture was stirred at room temperature for 2 h andconcentrated. The residue was dissolved in water and solid K₂CO₃ wasadded until the solution was basic. The aqueous solution was extractedwith dichloromethane (2×20 mL). The combined organic layers were driedover Na₂SO₄, filtered and concentrated to afford 1433, 1440, 1442 and1443.

# Compound Name Yield (%) 1440

(2S)-1-cyclohexyl-2-(5H-imidazo[5,1- a]isoindol-5-yl)ethyl2-aminopropanoate 87 ¹H NMR (a mixture of diastereomers) 0.96-1.06 (m,2H), 1.09-1.19 (m, 3H), 1.27 and 1.30 (two d, 3H, J = 7.0 Hz), 1.41-1.53(m, 3H), 1.63-1.77 (m, 5H), 2.10-2.16 and 2.23- 2.26 (two m, 1H),2.37-2.45 (m, 1H), 3.21 and 3.50 (two q, 1H, J = 7.0 Hz), 4.86-4.90,5.06-5.09 and 5.15-5.17 (three m, 2H), 7.19 (d, 1H, J = 3.2 Hz),7.24-7.27 (m, 1H, merged with chloroform), 7.37 (dt, 1H, J = 2.8, 7.6Hz), 7.49-7.55 (m, 2H), 7.69 (s, 1H) 1442

(2S)-1-cyclohexyl-2-(5H-imidazo[5,1- a]isoindol-5-yl)ethylpyrrolidine-2- carboxylate dihydrochloride 77 ¹H NMR (a mixture ofdiastereomers) (CD₃OD) 0.90-1.17 (m, 5H), 1.4-1.75 (m, 10H), 2.11-2.18(m, 2H), 2.36-2.42 (m, 1H), 2.82 (br s, 1H), 2.89-3.0 (m, 2H), 3.54-3.60and 3.72-3.75 and 3.81-3.83 (three m, 1H), 4.93-5.25 (four m, 2H), 7.16(s, 1H, J = 3.6 Hz), 7.22-7.16 (m, 1H), 7.35 (t, 1H, J = 7.40 Hz),7.48-7.52 (m, 2H), 7.69 (d, 1H, J = 8.40 Hz) 1443

(2S)-5-(1-cyclohexyl-2-(5H-imidazo[5,1- a]isoindol-5-yl)ethyl) 1-methyl2- aminopentanedioate dihydrochloride 73 ¹H NMR (a mixture ofdiastereomers) (DMOS-d6) 0.85-0.88 (m, 2H), 1.02-1.12 (m, 3H), 1.34-1.38(m, 1H), 1.53-1.67 (m, 5H), 2.14-2.20 (m, 2H), 2.60-2.73 (m, 2H),3.41-3.53 (m, 2H), 3.74 and 3.87 (two s, 3H), 4.44-4.52 (m, 1H),5.81-5.3 (m, 1H), 7.50-7.53 (m, 2H), 7.69-7.70 (m, 1H), 7.81-7.72 (m,1H), 7.95 (d, 1H, J= 6.4 Hz), 8.66 (br s, 3H), 9.52 (s, 1H) 1433

(2S)-1-(1-cyclohexyl-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethoxy)-3-methyl-1- oxobutan-2-aminium chloridehydrochloride 40 ¹H NMR (a mixture of diastereomers) (DMOS-d6) 0.86-0.98(m, 6H), 1.01-1.12 (m, 4H), 1.42 and 1.44 (two s, 9H), 1.58-1.87 (m,6H), 2.0-2.16 (m, 2H), 2.33-2.43 (m, 1H), 4.04- 4.07 and 4.08-4.15 (twom, 1H), 4.91-5.29 (three m, 3H), 7.17 (s, 1H), 7.21-7.28 (m, 2H),7.31-7.40 (m, 2H), 7.70 (s, 1H)

Biological Example 1 Human IDO Protein Cloning, Expression andPurification

Expression vectors for human indoleamine-2,3-dioxygenase (IDO) proteinwere prepared by amplification of a 1219 bp fragment of the sequencepresent in vector phIDO6His cDNA with primers5′-ggagcatgctaATGGCACACGCTATGGAAAAC-3′ and5′-gagagatctACCTTCCTTCAAAAGGGATTTC-3′ and cloning the SphI-BglII 1213 bpfragment into pQE70 (Qiagen), to yield vector pQE70-hIDO. This constructadds 2 extra amino acids and a 6-Histidine tag to the C-terminus of thenatural human IDO protein while preserving intact the natural startcodon and N-terminus amino acid sequence. The amplified allele of humanIDO shows two polymorphisms with respect to the sequence deposited inaccession file P14902 of SwissProt database. These polymorphisms resultin a P110S and E119G amino acid changes.

Plasmid pQE70-hIDO was transformed into M15 (pREP4) cells (Qiagen) andclones were selected in LB-agar plates supplemented with carbenicillin50 μg/mL and kanamycin 30 g/mL. Protein expression was carried out bygrowing an overnight culture of the M15pREP4/pQE70-hIDO clone in 100 mLLB supplemented with 100 μg/mL carbenicillin, 50 μg/mL kanamycin and 50μg/mL of L-tryptophan (LBCKT medium). 40 mL of this culture wereinoculated into 750 mL of LBCKT for 4 hours at 37° C. This culture wasdiluted 1:10 into LBCKT medium and cultured for another 2 hours at 37°C. until OD600 was higher than 0.8. At this point the cultures wereinoculated with Hemin to 7 M and L-Tryptophan to 75 μg/mL and incubatedat 37° C. for 2 h. Induction of protein expression was carried out bysupplementing the cultures with IPTG to 1 mM, PMSF to 200 μM, EDTA to 1mM and L-tryptophan to 50 μg/mL. Incubation was continued for additional16 h at 25° C. Cells were collected by centrifugation, and the cellpellets were washed with PBS buffer supplemented with 200 μM PMSF and 1mM EDTA and stored at −80° C. until protein purification.

The equivalent of 16 L of culture were processed in one batch ofpurification. Cell pellets were thawed, resuspended in 50 mM potassiumphosphate buffer pH 7.0, 200 μM PMSF, 1 mM EDTA, 1 mg/mL lysozyme to 10mL per liter of bacterial culture and incubated 30 minutes on ice. Cellswere then lysed by sonication. Cell lysates were centrifuged 20 min at20000 g and the supernatant was filtered through 0.45 μm filters. Thefiltered supernatant was loaded onto a 60 mL phosphocellulose columnequilibrated with 50 mM potassium phosphate buffer pH 6.5 (KPB) at 1-3mL/min. The column was washed with 3 volumes of 50 mM KPB, 3 volumes of100 mM. KPB and the protein was eluted with 15 volumes of a lineargradient of 100-500 mM KPB. Fractions were collected and IDO activityassay was performed by measuring kynurenine production. This was carriedout by mixing 50 μL of each fraction with 100 μL of reaction mix toyield a final concentration of 50 mM KPB buffer, 20 mM ascorbic acid,200 μg/mL catalase, 20 μM methylene blue and 400 μM L-tryptophan.Fractions demonstrating IDO activity were loaded onto a Ni-NTApurification column (15 mL). This affinity purification column waswashed with 10 volumes of 250 mM KPB, 150 mM NaCl, 50 mM imidazole pH 8,and eluted with 10 volumes of buffer containing 250 mM KPB, 150 mM NaCland a 50 to 250 mM imidazole linear gradient. Collected fractions wereassayed by IDO enzymatic assay described above and the positivefractions were pooled and concentrated by ultrafiltration and dialyzedagainst a buffer containing 250 mM KPB, 50% glycerol. This processyields-8-10 mg of pure protein (>98%) with a specific activity of 170mol/h/mg.

Biological Example 2 Testing of IDO Inhibitory Compounds by EnzymaticIDO Assay

The IC₅₀ values for each compound were determined by testing theactivity of IDO in a mixture containing 50 mM potassium phosphate bufferat pH 6.5; 70 nM purified human IDO protein, 200 μM L-tryptophan, 20 mMascorbate, 20 μM methylene blue, 0.1% DMSO. The inhibitors wereinitially diluted in DMSO at 100 mM and were diluted in potassiumphosphate 50 mM, added to the reaction mixture at final concentrationsraging from 1 mM to 5 nM and preincubated with the enzyme for 5 min at25° C. The reaction was started by addition of L-tryptophan to 200 μMand incubated 15 min at 37° C. The reaction was stopped by addition of0.5 vol of 30% trichloroacetic acid and incubated 30 min at 60° C. tohydrolyze N-formylkynurenine to kynurenine. The reaction was centrifugedat 3400 g for 5 min to remove precipitated protein and the supernatantwas reacted with 2% (w/v) of p-dimethylaminobenzaldehyde in acetic acid.The reaction was incubated 10 min at 25° C. and read at 480 nm in aspectrophotometer. Control samples with no IDO inhibitor, or with no IDOenzyme or with the reference inhibitors 1-methyl-tryptophan (200 M) andmenadione (1.2 μM) were used as controls to set the parameters for thenon-linear regressions necessary for determination of the IC₅₀ for eachcompound. Nonlinear regressions and determination of the IC₅₀ valueswere performed using the GraphPad Prism 4 software. Compounds with anIC₅₀ of less than 500 M were considered as active inhibitors in thisassay.

Biological Example 3 Determination of IDO Inhibitory Activity andToxicity in Cell Based IDO/Kynurenine Assay

293-T-REx™ cells (Invitrogen) constitutively express a tet operatorbinding repressor protein and are maintained in DMEM, 10% FBS, 1×Penicillin+Streptomycin, 2 mM L-glutamine, 5 μg/mL blasticidin at 37° C.with a 5% CO₂ in air atmosphere and typically split prior to confluency.Cells were passed by splitting the culture 1/10—by removing media byaspiration, washing 1× with PBS, incubating with 0.25% trypsin/EDTAuntil the cells detach, disbursing the cells in fresh growth media, andplating at 1/10 dilutions in fresh growth media. For long termcryopreservation, cells are detached from the plate as described above,collected by centrifugation, resuspended in freeze medium (growthmedium, 10% DMSO), stored in 1.8 mL cyropreservation vials (˜2−5×106cells per vial), in liquid nitrogen vapor storage tanks.

IDO1-expressing 293-T-Rex™ cell lines were generated by stabletransfection of plasmid pcDNA-tetO-IDO expressing human IDO or murineIDO under the control of the doxycycline-inducible CMV-tet promoter.Transfected cells were selected in DBZ medium (DMEM, 10% FBS, 1×Penicillin+Streptomycin, 2 mM L-glutamine, 5 μg/mL blasticidin and 25μg/mL Zeocin) at 37° C. with a 5% CO₂ in air atmosphere. Individualclones were isolated by limiting dilution cloning from thesepopulations. These clones were assayed for IDO activity and the clonesthat showed the highest levels of IDO activity inducible by doxycyclinewere used for subsequent cell based IDO assays.

To setup an IDO cell based activity assay, IDO-293-T-Rex cells wereharvested and resuspended in DBZ media at 10⁶ cells/mL, and split intopoly-D-lysine coated 96-well plates at 100,000 cells per well. 100 μL ofNeutral medium (DBZ medium, 200 μM L-tryptophan) or Induction media(Neutral medium supplemented with 5 μM doxycycline) are added to thecells and incubated 28 h at 37° C. After the IDO induction period,medium is removed and replaced with Induction or Neutral mediumcontaining different concentrations of each inhibitor (1 mM to 0.5 nM).The cells incubated in Neutral medium serve as negative control of theassay. The cells incubated in Induction medium and without inhibitorserve as the positive control of the assay. The incubation is carriedout for 16 h at 37° C. in a cell culture incubator. 200 μL of medium aretransferred to U-bottom polypropylene 96-well plates containing 25 μL of30% TCA, incubated 30 minutes at 60° C. and centrifuged at 3400 g for 5minutes. 150 μL of the clear supernatant is transferred to a polystyrene96-well plate containing 50 μL of 4% (w/v) ofp-dimethylaminobenzaldehyde in acetic acid, incubated for 10 min.Kynurenine concentration is determined by measuring the absorbance at480 nm.

To measure the toxicity of each compound after 16 h incubation withcells, cell viability is measured via a WST-1 assay (Roche) according toinstructions from the manufacturer. Briefly, after the incubation witheach compound, medium is aspirated and replaced with 100 mL of WST-1reagent, and incubated 30 min at 37° C. Absorbance at 540 nm iscorrelated with the number of viable cells. Determination of IC₅₀(Kynurenine assay) or LD₅₀ (WST-1 assay) is performed via non-linearregression analysis using GraphPad Prism software.

Biological Example 4 Reversal of IDO-Mediated Suppression of T-CellProliferation by IDO Inhibitors

Human monocytes were collected from peripheral mononuclear cells byleukoapheresis and cultured overnight at 10⁶ cells/well in a 96-wellplate in RPMI 1640 medium supplemented with 10% fetal calf serum and 2mM L-glutamine. Adherent cells were retained and cultured for 7 dayswith 200 ng/ml IL-4, 100 ng/ml GM-CSF. Cells were matured for 2 dayswith a cytokine cocktail containing TNF-α, IL-1β, IL-6 and PGE2 foradditional 2 days to induce dendritic cell maturation. At the end ofmaturation, loosely adherent cells were detached by gentle aspirationand plated in V-bottom 96 well plates, at 5000 cells/well. These cellsare >80% IDO+ dendritic cells. Human allogeneic T cells (3×10⁵) fromnormal donors were resuspended in RPMI 1640 supplemented with 100-200U/mL IL-2 and 100 ng/mL anti-CD3 antibody and added to the wells. Serialdilutions of IDO compounds dissolved in phenol red-free RPMI was addedto yield a final concentration of IDO1 between 500 and 1 μM. Afterincubation for 2-4 days, T cell proliferation was measured by BrdUincorporation assay after an overnight pulse with BrdU labeling mix(Roche Molecular Biochemicals). At the en of the pulse, the cells werefixed and incubated with 100 μL/well anti-BrdU-POD antibody followingthe instructions from the manufacturer. Plates were read in a microplatereader.

Alternatively, testing of IDO inhibitors in an in vitro mouse model ofIDO-mediated suppression of T cell proliferation is performed by thefollowing procedure. C57bl6 mice are inoculated with 1×10⁶ B78H1-GMCSFtumor cells in the right flank. After 10-12 days, tumor draining lymphnodes are collected and cells are stained with anti-CD11c and anti-B220monoclonal antibodies. Cells are sorted by high-speed fluorescenceactivated cell sorting and the CD11c+/B220+ plasmacytoid dendritic cellsare collected and seeded at 2000 cells/well in 96 well V-bottom plates.Splenocytes are collected from BM3 transgenic mice (in CBA background)and collected by nylon wool enrichment. BM3 T cells (10⁵ cells/well) areadded to each well in 200 μL of RPMI, 10% FCS, 50 μM β-mercaptoetanol.Alternatively, T cells are obtained from spleens of OT-I transgenic miceand added to the culture in combination with OVA peptide. IDO inhibitorsare added dissolved in RPMI at final concentrations ranging from 1 mM to10 nM. After 3 days of stimulation, cells are pulsed by 16 h with BrdUor ³H-thymidine. Cells are collected, fixed and tested for BrdUincorporation following the instructions from the BrdU labeling kitmanufacturer (Roche Diagnostics). If ³H-tymidine is used to measure Tcell proliferation, cells are harvested and dpm counts are measured in ascintillation counter following procedures widely known in the art.Control CD11c⁺ cells taken from the contralateral lymph node orCD11c⁺/B220⁻ cells (IDO⁻ population) from the TDLN are used as positivecontrol for proliferation.

Biological Example 5 Pharmacological Value

Pharmacological values for compounds tested according to one or more ofthe preceding examples are reported in the following table, including,

Human IDO IC₅₀: this is the concentration of the compound at which weobserve 50% of enzymatic activity using recombinant human IDO under theassay conditions described in one of the examples;

IC₅₀ values are reported in ranges: A: <1 μM, B: 1-10 μM, C: 10-100 μM;D: >100 μM.

hIDO No. Structure Name IC₅₀ 1254

2-(5H-imidazo[5,1-a]isoindol-5-yl)ethanol B 1256

ethyl 2-(5H-imidazo[5,1-a]isoindol-5- yl)acetate B 1258

2-(5H-imidazo[5,1-a]isoindol-5-yl)acetic acid D 1259

2-(5H-imidazo[5,1-a]isoindol-5-yl)-N- methylacetamide D 1273

(E)-5-(2-bromostyryl)-5H-imidazo[5,1- a]isoindole C 1286

2-(6-chloro-5H-imidazo[5,1-a]isoindol-5- yl)-1-cyclohexylethanol A 1287

2-(6-chloro-5H-imidazo[5,1-a]isoindol-5- yl)-1-cyclohexylethanone B 1288

2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl 2-(((1R,2R,5S)-2-isopropyl-5-methylcyclohexyl)oxy)acetate B 1299

2-(6-chloro-5H-imidazo[5,1-a]isoindol-5- yl)-1-cyclohexylethanol A 1300

tert-butyl (4-(2-(5H-imidazo[5,1-a]isoindol-5-yl)acetyl)phenyl)carbamate B 1301

1-(4-aminophenyl)-2-(5H-imidazo[5,1- a]isoindol-5-yl)ethanone C 1302

tert-butyl (4-(1-hydroxy-2-(5H- imidazo[5,1-a]isoindol-5-yl)ethyl)phenyl)carbamate A 1303

1-(4-aminophenyl)-2-(5H-imidazo[5,1- a]isoindol-5-yl)ethanol C 1304

1-cyclohexyl-2-(5H-imidazo[5,1- a]isoindol-5-yl)ethanol A 1306

2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(3- nitrophenyl)ethanone B 1307

2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(3- nitrophenyl)ethanol A 1326

2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(2- nitrophenyl)ethanone B 1327

2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(2- nitrophenyl)ethanol A 1328

tert-butyl (2-(2-(5H-imidazo[5,1-a]isoindol-5-yl)acetyl)phenyl)carbamate B 1329

tert-butyl (2-(1-hydroxy-2-(5H- imidazo[5,1-a]isoindol-5-yl)ethyl)phenyl)carbamate B 1330

1-(2-aminophenyl)-2-(5H-imidazo[5,1- a]isoindol-5-yl)ethanone B 1331

1-(2-aminophenyl)-2-(5H-imidazo[5,1- a]isoindol-5-yl)ethanol A 1334

1-(2-chlorophenyl)-2-(5H-imidazo[5,1- a]isoindol-5-yl)ethanone B 1335

1-(5H-imidazo[5,1-a]isoindol-5-yl)-2- methylpropan-2-ol B 1336

1-(2-chlorophenyl)-2-(5H-imidazo[5,1- a]isoindol-5-yl)ethanol A 1343

1-(3-chlorophenyl)-2-(5H-imidazo[5,1- a]isoindol-5-yl)ethanol A 1348

2-(5H-imidazo[5,1-a]isoindol-5-yl)-1- phenylethanone B 1349

2-(5H-imidazo[5,1-a]isoindol-5-yl)-1- phenylethanol A 1352

1-(2,4-dimethylfuran-3-yl)-2-(6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)ethanol; B 1353

1-(3-chlorophenyl)-2-(5H-imidazo[5,1- a]isoindol-5-yl)ethanone B 1356

1-cyclohexyl-2-(6-fluoro-5H-imidazo[5,1- a]isoindol-5-yl)ethanone B 1357

1-cyclohexyl-2-(6-fluoro-5H-imidazo[5,1- a]isoindol-5-yl)ethanol A 1358

2-(5H-imidazo[5,1-a]isoindol-5-yl)-1- (tetrahydro-2H-pyran-4-yl)ethanolA 1359

2-(7-chloro-5H-imidazo[5,1-a]isoindol-5- yl)-1-cyclohexylethanol A 1360

(Z)-1-cyclohexyl-2-(5H-imidazo[5,1- a]isoindol-5-yl)ethanone oxime B1362

1-cyclopentyl-2-(5H-imidazo[5,1- a]isoindol-5-yl)ethanol A 1363

tert-butyl 4-(1-hydroxy-2-(5H- imidazo[5,1-a]isoindol-5-yl)ethyl)piperidine-1-carboxylate A 1364

1-cyclohexyl-2-(5H-imidazo[5,1- a]isoindol-5-yl)ethanamine B 1367

tert-butyl (3-(1-hydroxy-2-(5H- imidazo[5,1-a]isoindol-5-yl)ethyl)phenyl)carbamate B 1369

1-(3-aminophenyl)-2-(5H-imidazo[5,1- a]isoindol-5 -yl)ethanol B 1370

2-(5H-imidazo[5,1-a]isoindol-5-yl)-1- (piperidin-4-yl)ethanol D 1371

4-(2-(6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-1-hydroxyethyl)cyclohexanol; A 1372

1-cyclohexyl-2-(9-methoxy-5H- imidazo[5,1-a]isoindol-5-yl)ethanol C 1373

5-(2-cyclohexyl-2-hydroxyethyl)-5H- imidazo[5,1-a]isoindol-9-ol C 1374

2-(8-chloro-5H-imidazo[5,1-a]isoindol-5- yl)-1-cyclohexylethanol; B 1375

1-(cyclohex-1-en-1-yl)-2-(5H- imidazo[5,1-a]isoindol-5-yl)ethanol; B1376

1-cyclohexyl-2-(8-fluoro-5H-imidazo[5,1- a]isoindol-5-yl)ethanol; B 1378

2-(6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-1-(1,4-dioxaspiro[4.5]decan-8- yl)ethanol; B 1379

4-(2-(6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-1-hydroxyethyl)cyclohexanone; A 1381

2-(6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-1-(4-methylenecyclohexyl)ethanol; A 1382

1-(cyclohex-3-en-1-yl)-2-(5H- imidazo[5,1-a]isoindol-5-yl)ethanol; A1383

1-(4-(hydroxymethyl)cyclohexyl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethanol; A 1384

(4-(1-hydroxy-2-(5H-imidazo[5,1- a]isoindol-5-yl)ethyl)piperidin-1-yl)(thiophen-2-yl)methanone; A 1385

1-(4-(1-hydroxy-2-(5H-imidazo[5,1- a]isoindol-5-yl)ethyl)piperidin-1-yl)ethanone; B 1386

2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(4- methylenecyclohexyl)ethanol; A1387

2-(6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-1-(4-methylcyclohexyl)ethanol; A 1388

1-cyclohexyl-2-(5H-imidazo[5,1- a]isoindol-5-yl)ethanamine B 1389

2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(1-methyl-1H-imidazol-4-yl)ethanol; D 1390

2-(5H-imidazo[5,1-a]isoindol-5-yl)-1- (thiazol-4-yl)ethanol; C 1391

2-(5H-imidazo[5,1-a]isoindol-5-yl)-1- (thiazol-5-yl)ethanol; B 1392

1-(4-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)piperidin-1-yl)-2,2- dimethylpropan-1-one; B 1393

2-(6-fluoro-5H-imidazo[5,1-a]isoindol-5- yl)-1-(furan-2-yl)ethanol; B1394

2-(6-fluoro-5H-imidazo[5,1-a]isoindol-5- yl)-1-(1-methyl-1H-imidazol-2-yl)ethanol; C 1398

2-(6-fluoro-5H-imidazo[5,1-a]isoindol-5- yl)-1-(4-(iodomethylene)cyclohexyl)ethanol; A 1400

1-cyclohexyl-2-(5H-imidazo[5,1- a]isoindol-5-yl)propan-1-ol; B 1402

2-(5H-imidazo[5,1-a]isoindol-5- yl)acetonitrile; C 1403

1-cyclohexyl-3-(6-fluoro-5H-imidazo[5,1- a]isoindol-5-yl)propan-2-ol; A1404

1-cyclohexyl-3-(5H-imidazo[5,1- a]isoindol-5-yl)propan-2-ol; A 1405

1-(4-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)piperidin-1-yl)-2- phenylethanone; A 1406

1-(4,4-difluorocyclohexyl)-2-(6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)ethanol; A 1407

1-(4,4-difluorocyclohexyl)-2-(5H- imidazo[5,1-a]isoindol-5-yl)ethanol; A1409

2-(6-fluoro-5H-imidazo[5,1-a]isoindol-5- yl)-1-(1-methyl-1H-imidazol-5-yl)ethanol; C 1410

1-(4-(cyclopropylmethylene)cyclohexyl)-2-(6-fluoro-5H-imidazo[5,1-a]isoindol-5- yl)ethanol; A 1411

2-(6-fluoro-5H-imidazo[5,1-a]isoindol-5- yl)-1-(4-(propan-2-ylidene)cyclohexyl)ethanol; A 1412

(E)-5-(2-cyclohexylvinyl)-5H- imidazo[5,1-a]isoindole; A 1413

2-(9-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-1-(4-methylcyclohexyl)ethanol; A 1414

1-(cyclohex-3-en-1-yl)-2-(6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)ethanol; A 1415

(R)-1-cyclohexyl-2-((R)-5H-imidazo[5,1- a]isoindol-5-yl)ethanol B 1416

(S)-1-cyclohexyl-2-((R)-5H-imidazo[5,1- a]isoindol-5-yl)ethanol B 1417

(S)-1-cyclohexyl-2-((S)-5H-imidazo[5,1- a]isoindol-5-yl)ethanol A 1418

(R)-1-cyclohexyl-2-((S)-5H-imidazo[5,1- a]isoindol-5-yl)ethanol A 1419

1-cyclohexyl-2-(5H-imidazo[5,1- a]isoindol-5-ylidene)ethanol B 1420

1-cyclohexyl-2-(5H-imidazo[5,1- a]isoindol-5-yl)ethyl acetate C 1421

1-(4-(2- (benzyloxy)ethylidene)cyclohexyl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethanol A 1422

1-(1-(benzylsulfonyl)piperidin-4-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethanol A 1423

1-(4-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)piperidin-1-yl)-2- (pyrimidin-5-yl)ethanone A 1424

2-(3,4-difluorophenyl)-1-(4-(1-hydroxy-2- (5H-imidazo[5,1-a]isoindol-5-yl)ethyl)piperidin-1-yl)ethanone A 1425

cyclohexyl(4-(1-hydroxy-2-(5H- imidazo[5,1-a]isoindol-5-yl)ethyl)piperidin-1-yl)methanone A 1426

methyl 4-(1-hydroxy-2-(5H-imidazo[5,1- a]isoindol-5-yl)ethyl)cyclohexanecarboxylate A 1427

1-cyclohexyl-2-(5H-imidazo[5,1- a]isoindol-5-yl)ethyl phenylcarbamate B1428

4-(1-cyclohexyl-2-(5H-imidazo[5,1- a]isoindol-5-yl)ethoxy)-4-oxobutanoicacid B 1429

4-(1-hydroxy-2-(5H-imidazo[5,1- a]isoindol-5-yl)ethyl)cyclohexanol A1430

1-(4-(hydroxymethyl)cyclohexyl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethanol A 1431

1-cyclohexyl-2-(5H-imidazo[5,1- a]isoindol-5-yl)ethyl benzoate C 1432

4-(1-hydroxy-2-(5H-imidazo[5,1- a]isoindol-5-yl)ethyl)-N-(2-(methylsulfonamido)ethyl) cyclohexanecarboxamide B 1433

(2S)-1-(1-cyclohexyl-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethoxy)-3-methyl-1- oxobutan-2-aminium chloride C 1434

sodium 1-cyclohexyl-2-(5H-imidazo[5,1- a]isoindol-5-yl)ethyl phosphate A1436

4-(1-hydroxy-2-(5H-imidazo[5,1- a]isoindol-5-yl)ethyl)cyclohexanecarboxylic acid B 1437

1-(4-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)piperidin-1-yl)-2- (pyridin-4-yl)ethanone A 1438

2-(5H-imidazo[5,1-a]isoindol-5-yl)-1- (spiro[2.5]octan-6-yl)ethanol C1439

2-(4-fluorophenyl)-1-(4-(1-hydroxy-2- (5H-imidazo[5,1-a]isoindol-5-yl)ethyl)piperidin-1-yl)ethanone A 1440

(2S)-1-cyclohexyl-2-(5H-imidazo[5,1- a]isoindol-5-yl)ethyl2-aminopropanoate C 1441

1-(4-(2-hydroxyethylidene)cyclohexyl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethanol A 1442

(2S)-1-cyclohexyl-2-(5H-imidazo[5,1- a]isoindol-5-yl)ethylpyrrolidine-2- carboxylate B 1443

(2S)-5-(1-cyclohexyl-2-(5H-imidazo[5,1- a]isoindol-5-yl)ethyl) 1-methyl2- aminopentanedioate C 1447

1-(4-((S)-1-hydroxy-2-((S)-5H- imidazo[5,1-a]isoindol-5-yl)ethyl)piperidin-1-yl)-2-phenylethanone A 1448

(3-fluoro-2-hydroxyphenyl)(4-(1- hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)piperidin-1-yl)methanone A 1449

4-(1-hydroxy-2-(5H-imidazo[5,1- a]isoindol-5-yl)ethyl)-N-phenylpiperidine-1-carboxamide A 1450

(4-fluorophenyl)(4-(1-hydroxy-2-(5H- imidazo[5,1-a]isoindol-5-yl)ethyl)piperidin-1-yl)methanone B 1451

(2S)-2-amino-1-(4-(1-hydroxy-2-(5H- imidazo[5,1-a]isoindol-5-yl)ethyl)piperidin-1-yl)-3-phenylpropan- 1-one B 1454

(4-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)piperidin-1-yl)((S)- pyrrolidin-2-yl)methanone D1455

(1R,4s)-4-(2-((S)-6-fluoro-5H- imidazo[5,1-a]isoindol-5-yl)-1-hydroxyethyl)cyclohexyl benzoate A 1456

(1R,4s)-4-(2-((S)-6-fluoro-5H- imidazo[5,1-a]isoindol-5-yl)-1-hydroxyethyl)cyclohexanol A 1458

1-(3-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)azetidin-1-yl)-2- phenylethanone A 1459

3-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)-N-phenylazetidine- 1-carboxamide A 1460

tert-butyl 3-(1-hydroxy-2-(5H- imidazo[5,1-a]isoindol-5-yl)ethyl)azetidine-1-carboxylate A 1461

1-(azetidin-3-yl)-2-(5H-imidazo[5,1- a]isoindol-5-yl)ethanol C 1469

tert-butyl 4-((S)-1-hydroxy-2-((R)-5H- imidazo[5,1-a]isoindol-5-yl)ethyl)piperidine-1-carboxylate B 1470

tert-butyl 4-((R)-1-hydroxy-2-((R)-5H- imidazo[5,1-a]isoindol-5-yl)ethyl)piperidine-1-carboxylate B 1471

tert-butyl 4-((R)-1-hydroxy-2-((S)-5H- imidazo[5,1-a]isoindol-5-yl)ethyl)piperidine-1-carboxylate A 1472

tert-butyl 4-((S)-1-hydroxy-2-((S)-5H- imidazo[5,1-a]isoindol-5-yl)ethyl)piperidine-1-carboxylate A 1473

1-((1s,4s)-4-(benzyloxy)cyclohexyl)-2-((6-fluoro-5H-imidazo[5,1-a]isoindol-5- yl)ethanol A 1474

2-(5H-imidazo[5,1-a]isoindol-5-yl)-1- (pyridin-3-yl)ethanol B 1475

(1r,4r)-4-(2-(6-fluoro-5H-imidazo[5,1- a]isoindol-5-yl)-1-hydroxyethyl)cyclohexanol A 1476

4-((S)-1-hydroxy-2-((R)-5H-imidazo[5,1- a]isoindol-5-yl)ethyl)-N-phenylpiperidine-1-carboxamide B 1477

4-((R)-1-hydroxy-2-((R)-5H-imidazo[5,1- a]isoindol-5-yl)ethyl)-N-phenylpiperidine-1-carboxamide B 1478

4-((R)-1-hydroxy-2-((S)-5H-imidazo[5,1- a]isoindol-5-yl)ethyl)-N-phenylpiperidine-1-carboxamide A 1479

4-((S)-1-hydroxy-2-((S)-5H-imidazo[5,1- a]isoindol-5-yl)ethyl)-N-phenylpiperidine-1-carboxamide A 1480

1-(4-((R)-1-hydroxy-2-((S)-5H- imidazo[5,1-a]isoindol-5-yl)ethyl)piperidin-1-yl)-2-phenylethanone A 1481

1-(4-((S)-1-hydroxy-2-((S)-5H- imidazo[5,1-a]isoindol-5-yl)ethyl)piperidin-1-yl)-2-phenylethanone A 1482

(1R,4s)-4-((S)-2-((R)-6-fluoro-5H- imidazo[5,1-a]isoindol-5-yl)-1-hydroxyethyl)cyclohexanol B 1483

(1S,4s)-4-((R)-2-((R)-6-fluoro-5H- imidazo[5,1-a]isoindol-5-yl)-1-hydroxyethyl)cyclohexanol B 1484

(1S,4s)-4-((R)-2-((S)-6-fluoro-5H- imidazo[5,1-a]isoindol-5-yl)-1-hydroxyethyl)cyclohexanol A 1485

(1R,4s)-4-((S)-2-((S)-6-fluoro-5H- imidazo[5,1-a]isoindol-5-yl)-1-hydroxyethyl)cyclohexanol A 1486

(1S,4r)-4-((S)-2-((S)-6-fluoro-5H- imidazo[5,1-a]isoindol-5-yl)-1-hydroxyethyl)cyclohexanol A 1487

(1S,4r)-4-((S)-2-((R)-6-fluoro-5H- imidazo[5,1-a]isoindol-5-yl)-1-hydroxyethyl)cyclohexanol B 1488

(1R,4r)-4-((R)-2-((S)-6-fluoro-5H- imidazo[5,1-a]isoindol-5-yl)-1-hydroxyethyl)cyclohexanol A 1489

(1R,4r)-4-((R)-2-((R)-6-fluoro-5H- imidazo[5,1-a]isoindol-5-yl)-1-hydroxyethyl)cyclohexanol B 1490

1-(4-((S)-1-hydroxy-2-((S)-5H- imidazo[5,1-a]isoindol-5-yl)ethyl)piperidin-1-yl)-2-(tetrahydro-2H- pyran-4-yl)ethanone A 1491

1-(4-((R)-1-hydroxy-2-((R)-5H- imidazo[5,1-a]isoindol-5-yl)ethyl)piperidin-1-yl)-2-phenylethanone B 1492

N-((1s,4s)-4-(1-hydroxy-2-(5H- imidazo[5,1-a]isoindol-5-yl)ethyl)cyclohexyl)benzamide A 1493

1-(4-((S)-1-hydroxy-2-((R)-5H- imidazo[5,1-a]isoindol-5-yl)ethyl)piperidin-1-yl)-2-phenylethanone B 1494

2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(1-(phenylcarbamoyl)piperidin-4-yl)ethyl phenylcarbamate C 1495

4-((R)-1-hydroxy-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)ethyl)-N-((1r,4R)-4- hydroxycyclohexyl)piperidine-1-carboxamide A 1496

4-((S)-1-hydroxy-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)ethyl)-N-(tetrahydro-2H-pyran-4-yl)piperidine-1-carboxamide A 1497

4-((S)-1-hydroxy-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)ethyl)-N-((1r,4S)-4- hydroxycyclohexyl)piperidine-1-carboxamide A 1498

1-((1r,4r)-4-(benzyloxy)cyclohexyl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethanol A 1499

1-((1r,4r)-4-(benzyloxy)cyclohexyl)-2-(6-fluoro-5H-imidazo[5,1-a]isoindol-5- yl)ethanol A 1500

1-(4-((R)-1-hydroxy-2-((S)-5H- imidazo[5,1-a]isoindol-5-yl)ethyl)piperidin-1-yl)-2-(tetrahydro-2H- pyran-4-yl)ethanone A 1501

2-(5H-imidazo[5,1-a]isoindol-5-yl)-1- (pyridin-4-yl)ethanol A 1502

2-(5H-imidazo[5,1-a]isoindol-5-yl)-1- (pyridin-2-yl)ethanol B 1503

4-((R)-1-hydroxy-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)ethyl)-N-(tetrahydro-2H-pyran-4-yl)piperidine-1-carboxamide A 1504

N-cyclohexyl-4-((R)-1-hydroxy-2-((S)- 5H-imidazo[5,1-a]isoindol-5-yl)ethyl)piperidine-1-carboxamide A 1505

N-((1r,4r)-4-(1-hydroxy-2-(5H- imidazo[5,1-a]isoindol-5-yl)ethyl)cyclohexyl)benzamide A 1506

1-((1r,4r)-4-(benzyloxy)cyclohexyl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethanol A 1507

N-cyclopentyl-4-((R)-1-hydroxy-2-((S)- 5H-imidazo[5,1-a]isoindol-5-yl)ethyl)piperidine-1-carboxamide A 1508

2-(6-fluoro-5H-imidazo[5,1-a]isoindol-5- yl)-1-(4-(trifluoromethyl)cyclohexyl)ethanol A 1509

2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(4-(trifluoromethyl)cyclohexyl)ethanol A 1511

1-(4-((R)-1-hydroxy-2-((S)-5H- imidazo[5,1-a]isoindol-5-yl)ethyl)piperidin-1-yl)-2-(4- (trifluoromethyl)phenyl)ethanone A 1512

4-((R)-1-hydroxy-2-((S)-5H-imidazo[5,1- a]isoindol-5-yl)ethyl)-N-(4-(trifluoromethyl)phenyl)piperidine-1- carboxamide A 1513

(4-((R)-1-hydroxy-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)ethyl)piperidin-1-yl)(1H- imidazol-1-yl)methanone

Biological Example 6 In Vivo Testing of IDO Inhibitors for AntitumorActivity in Combination with Chemotherapeutic Agents

In vivo anti-tumor efficacy can be tested using modified tumor allograftprotocols. For instance, it has been described in the literature thatIDO inhibition can syngerize with cytotoxic chemotherapy inimmune-competent mice. Due to different susceptibilities of differenttumor cell lines to chemotherapeutic drugs and to immune mediatedrejection, each IDO inhibitor is tested alone and in combination with 2different chemotherapeutic drugs in 4 different animal tumor models,represented by 4 different mouse tumor cell lines, of different tissueorigin (colorectal, bladder, mammary and lung carcinoma), implantedsubcutaneously in syngeneic strains of mice. These cell lines have beenselected based on their known susceptibility to chemotherapeutic drugs,their partial response to IDO inhibitors as single agents, theirpresumed pattern of IDO expression according to their tissue of origin,and their ability to elicit an immune reaction.

For every animal tumor model, 2 different chemotherapeutic drugs aretested in separate groups of mice according to the following list: 1]LLC tumor: cyclophosphamide and paclitaxel; 2] EMT6 tumor:cyclophosphamide and paclitaxel; 3] CT26 tumor: cyclophosphamide anddoxorubicin; and 4] MB49 tumor: cyclophosphamide and gemcitabine.

The following chemotherapeutic drugs are used, at the indicated doses.The maximum tolerated dose for the following chemotherapeutic agents inmice depends on the formulation, concentration, frequency ofadministration, route of administration and number of doses. Thechemotherapeutic drugs administered in conjunction with each IDOinhibitor drug are: 1] Paclitaxel: 20 mg/kg/day i.p, every 4 days, 4times (q4d×4) (in Cremophor); 2] Doxorubicin: 5 mg/kg, once a week for 3weeks (q7d×3); 3] Cyclophosphamide (CTX): 100 mg/kg, I.P., every 4 days,4 times (q4d×4); 4] Gemcitabine: 80 mg/kg every 4 days, 4 times, i.p.(q4d×4).

All animals receive a subcutaneous injection of a tumor forming dose oflive tumor cells (˜50000-1000000 cells) suspended in 0.1 mL of PBS orsaline on day 1. Subcutaneous injection forms a localized tumor thatallows monitoring tumor growth over time.

To mimic the effect of IDO inhibitor drugs as therapeutic compositions,administration of IDO inhibitor drugs begins at day 5-8 after tumorinoculation. Dosing, route of administration, dosing frequency variesdepending on the toxicity and pharmacokinetics profile of each drug.Duration of the treatment is 2 weeks. Most preferably, drug isadministered continuously via oral gavage or dissolution in the drinkingwater. Alternatively, subcutaneous slow release pellets or osmotic pumpscontaining 100 mg of each drug are implanted under the skin by surgicalprocedure. IDO inhibitor drug are administered at the maximum tolerateddose or at a concentration corresponding to the LD₅₀.

An example of antitumor activity is shown in FIGS. 1-2 (for Cpd#1357)and FIGS. 3-4 (for Cpd#1304). In this test, 200000 LLC murine tumorcells were injected subcutaneously into syngeneic C57B16 mice on day 0.Each treatement group consists of 10 mice. On day 7, once the tumor isestablished and IDO expression is induced in plasmacytoid dendriticcells at the tumor draining lymph nodes, a group of 10 mice weresurgically implanted (subcutaneously and on the opposite flank to thetumor), with osmotic pumps loaded with 200 uL of a 30 mg/mL solution ofcompounds 1357 or 1304 in cremaphor:EtOH:saline (10:10:80). These pumpsrelease 1 uL of solution per hour for a period of 8 days, achieveing asteady state plasma concentration of drug of ˜0.5-3 micromolar. Fromdays 15 to 24 compound administrations continued via two s.c. dailydoses of 1 mg each. In the case of FIGS. 3-4, mice were optionallytreated with cyclophosphamide 100 mg/kg by intraperitoneal injection ondays 9, 13 and 15 post-tumor innoculation, either as a single agent orin combination with compound 1304. The results of these tests indicatethat compounds 1357 and 1304 have a significant antitumor effect eitheras a single agent or when administered in combination with chemotherapy.The therapeutic effect is observed as a reduced rate of tumor growth,which has an impact on median survival time and in overall survivalfraction.

FIG. 1 shows the average tumor volume over time of two groups of 10 miceeach. The control group was treated with vehicle, while the treatmentgroups received osmotic pumps with compound 1357 as described above. Thetumor volumes were fitted to an exponential growth equation and thefitted parameters were compared using GraphPad software. The dataindicate a statistically significant differences between the two curves(p<0.0001).

FIG. 2 shows the survival plot of the same groups of mice described inFIG. 1. The logrank test indicates a statistically significantdifference in median survival time when animals were treated withcompound 1357 as a single agent.

FIG. 3 shows the average tumor volume over time of four groups of 10mice each. The control group was treated with vehicle, while thetreatment groups received either cyclophosphamide chemotherapy, osmoticpumps with compound 1304, or a combination therapy of cyclophosphamidewith compound 1304. The data shows that this tumor is very sensitive tothe effects of treatment with compound 1304 either as a single agent orin combination with chemotherapy.

FIG. 4 shows the survival plot of the same groups of mice described inFIG. 3. The logrank test indicated a statistically significantdifference in median survival time when animals were treated withcompound 1304, either as a single agent or in combination withcyclophosphamide. The long term survival fraction observed for treatmentwith 1304 is exceptionally high, with 70-80% of the mice being tumorfree after 60 days.

We claim:
 1. A compound selected from the group consisting of1-cyclohexyl-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethanol, tert-butyl4-((R)-1-hydroxy-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)ethyl)piperidine-1-carboxylate,(3-fluoro-2-hydroxyphenyl)(4-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)piperidin-1-yl)methanone,(S)-1-cyclohexyl-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)ethanol,4-((R)-1-hydroxy-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)ethyl)-N-phenylpiperidine-1-carboxamide,4-((S)-1-hydroxy-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)ethyl)-N-phenylpiperidine-1-carboxamide,(1R,4r)-4-((R)-2-((S)-6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-1-hydroxyethyl)cyclohexanol,1-(4-((S)-1-hydroxy-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)ethyl)piperidin-1-yl)-2-phenylethanone,N-cyclopentyl-4-((R)-1-hydroxy-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)ethyl)piperidine-1-carboxamide,4-((R)-1-hydroxy-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)ethyl)-N-(4-(trifluoromethyl)phenyl)piperidine-1-carboxamide,4-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)-N-phenylpiperidine-1-carboxamide,3-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)-N-phenylazetidine-1-carboxamide1459 tert-butyl4-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)piperidine-1-carboxylate1-(4-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)piperidin-1-yl)-2-(pyrimidin-5-yl)ethanone,1-(4-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)piperidin-1-yl)-2-(pyridin-4-yl)ethanone,1-(3-(1-hydroxy-2-(SH-imidazo[5,1-a]isoindol-5-yl)ethyl)azetidin-1-yl)-2-phenylethanone,and1-(4-((R)-1-hydroxy-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)ethyl)piperidin-1-yl)-2-(4-(trifluoromethyl)phenyl)ethanone.